Quinazolinone derivatives useful as FGFR kinase modulators

ABSTRACT

The invention relates to new quinazolinone derivative compounds, to pharmaceutical compositions comprising said compounds, to processes for the preparation of said compounds and to the use of said compounds in the treatment of diseases, e.g. cancer.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a national stage filing under section 371 ofInternational Application No. PCT/GB2014/051288, filed on Apr. 25, 2014,and published in English on Oct. 30, 2014 as WO 2014/174307, and claimspriority to British Application No. 1307577.5, filed on Apr. 26, 2013.The entire disclosures of each of the prior applications are herebyincorporated herein by reference.

FIELD OF THE INVENTION

The invention relates to new quinazolinone derivative compounds, topharmaceutical compositions comprising said compounds, to processes forthe preparation of said compounds and to the use of said compounds inthe treatment of diseases, e.g. cancer.

SUMMARY OF THE INVENTION

According to a first aspect of the invention there is provided compoundsof formula (I):

including any tautomeric or stereochemically isomeric form thereof,wherein

W is —N(R³)— or —C(R^(3a)R^(3b))—;

each R² is independently selected from hydroxyl, halogen, cyano,C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy, hydroxyC₁₋₄alkyl,hydroxyC₁₋₄alkoxy, haloC₁₋₄alkyl, haloC₁₋₄alkoxy, hydroxyhaloC₁₋₄alkyl,hydroxyhaloC₁₋₄alkoxy, C₁₋₄alkoxyC₁₋₄alkyl, haloC₁₋₄alkoxyC₁₋₄alkyl,C₁₋₄alkoxyC₁₋₄alkyl wherein each C₁₋₄alkyl may optionally be substitutedwith one or two hydroxyl groups, hydroxyhaloC₁₋₄alkoxyC₁₋₄alkyl, R¹³,C₁₋₄alkyl substituted with R¹³, C₁₋₄alkyl substituted with —C(═O)—R¹³,C₁₋₄alkoxy substituted with R¹³, C₁₋₄alkoxy substituted with —C(═O)—R¹³,—C(═O)—R¹³, C₁₋₄alkyl substituted with —NR⁷R⁸, C₁₋₄alkyl substitutedwith —C(═O)—NR⁷R⁸, C₁₋₄alkoxy substituted with —NR⁷R⁸, C₁₋₄alkoxysubstituted with —C(═O)—NR⁷R⁸, —NR⁷R⁸ and —C(═O)—NR⁷R⁸; or when two R²groups are attached to adjacent carbon atoms they may be taken togetherto form a radical of formula:—O—(C(R¹⁷)₂)_(p)—O—;—X—CH═CH—; or—X—CH═N—;

-   -   wherein R¹⁷ represents hydrogen or fluorine, p represents 1 or 2        and X represents O or S;

D represents a 3 to 12 ring membered monocyclic or bicyclic carbocyclylor a 3 to 12 ring membered monocyclic or bicyclic heterocyclylcontaining at least one heteroatom selected from N, O or S, wherein saidcarbocyclyl and heterocyclyl may each be optionally substituted by oneor more (e.g. 1, 2 or 3) R¹ groups;

R¹ represents hydrogen, halo, cyano, C₁₋₆alkyl, C₁₋₆alkoxy,—C(═O)—O—C₁₋₆alkyl, C₂₋₄alkenyl, hydroxyC₁₋₆alkyl, haloC₁₋₆alkyl,hydroxyhaloC₁₋₆alkyl, cyanoC₁₋₄alkyl, C₁₋₆alkoxyC₁₋₆alkyl wherein eachC₁₋₆alkyl may optionally be substituted with one or two hydroxyl groups,—NR⁴R⁵, C₁₋₆alkyl substituted with —O—C(═O)—C₁₋₆alkyl, C₁₋₆alkylsubstituted with —NR⁴R⁵, —C(═O)—NR⁴R⁵, —C(═O)—C₁₋₆alkyl-NR⁴R⁵, C₁₋₆alkylsubstituted with —C(═O)—NR⁴R⁵, —S(═O)₂—C₁₋₆alkyl, —S(═O)₂-haloC₁₋₆alkyl,—S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with —S(═O)₂—C₁₋₆alkyl, C₁₋₆alkylsubstituted with —S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with—S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with —NH—S(═O)₂—C₁₋₆alkyl,C₁₋₆alkyl substituted with —NH—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkylsubstituted with —NR¹²—S(═O)₂—NR¹⁴R¹⁵, R⁶, C₁₋₆alkyl substituted withR⁶, —C(═O)—R⁶, C₁₋₆alkyl substituted with —C(═O)—R⁶, hydroxyC₁₋₆alkylsubstituted with R⁶, C₁₋₆alkyl substituted with —Si(CH₃)₃, C₁₋₆alkylsubstituted with —P(═O)(OH)₂ or C₁₋₆alkyl substituted with—P(═O)(OC₁₋₆alkyl)₂;

R^(3a) represents —NR¹⁰R¹¹, hydroxyl, C₁₋₆alkoxy, hydroxyC₁₋₆alkoxy,C₁₋₆alkoxy substituted with —NR¹⁰R¹¹, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, haloC₁₋₆alkyl optionally substituted with—O—C(═O)—C₁₋₆alkyl, hydroxyC₁₋₆alkyl optionally substituted with—O—C(═O)—C₁₋₆alkyl, hydroxyC₂₋₆alkenyl, hydroxyC₂₋₆alkynyl,hydroxyhaloC₁₋₆alkyl, cyanoC₁₋₆alkyl, C₁₋₆alkyl substituted withcarboxyl, C₁₋₆alkyl substituted with —C(═O)—C₁₋₆alkyl, C₁₋₆alkylsubstituted with —C(═O)—O—C₁₋₆alkyl, C₁₋₆alkyl substituted withC₁₋₆alkoxyC₁₋₆alkyl-O—C(═O)—, C₁₋₆alkyl substituted withC₁₋₆alkoxyC₁₋₆alkyl-C(═O)—, C₁₋₆alkyl substituted with—O—C(═O)—C₁₋₆alkyl, C₁₋₆alkoxyC₁₋₆alkyl wherein each C₁₋₆alkyl mayoptionally be substituted with one or two hydroxyl groups or with—O—C(═O)—C₁₋₆alkyl, C₂₋₆alkenyl substituted with C₁₋₆alkoxy, C₂₋₆alkynylsubstituted with C₁₋₆alkoxy, C₁₋₆alkyl substituted with R⁹ andoptionally substituted with —O—C(═O)—C₁₋₆alkyl, C₁₋₆alkyl substitutedwith —C(═O)—R⁹, C₁₋₆alkyl substituted with hydroxyl and R⁹, C₂₋₆alkenylsubstituted with R⁹, C₂₋₆alkynyl substituted with R⁹, C₁₋₆alkylsubstituted with —NR¹⁰R¹¹, C₂₋₆alkenyl substituted with —NR¹⁰R¹¹,C₂₋₆alkynyl substituted with —NR¹⁰R¹¹, C₁₋₆alkyl substituted withhydroxyl and —NR¹⁰R¹¹, C₁₋₆alkyl substituted with one or two halogensand —NR¹⁰R¹¹, —C₁₋₆alkyl-C(R¹²)═N—O—R¹², C₁₋₆alkyl substituted with—C(═O)—NR¹⁰R¹¹, C₁₋₆alkyl substituted with —O—C(═O)—NR¹⁰R¹¹,—S(═O)₂—C₁₋₆alkyl, —S(═O)₂-haloC₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkylsubstituted with —S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with —S(═O)₂—NR¹⁴R¹⁵,C₁₋₆alkyl substituted with —NR¹²—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substitutedwith —NH—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with—NR¹²—S(═O)₂—NR¹⁴R¹⁵, R¹³, C₁₋₆alkyl substituted with —P(═O)(OH)₂ orC₁₋₆alkyl substituted with —P(═O)(OC₁₋₆alkyl)₂;

R^(3b) represents hydrogen or hydroxyl; provided that if R^(3a)represents —NR¹⁰R¹¹, then R^(3b) represents hydrogen; or

R^(3a) and R^(3b) are taken together to form ═O, to form ═NR¹⁰, to formcyclopropyl together with the carbon atom to which they are attached, toform ═CH—C₀₋₄alkyl substituted with R^(3c), or to form

wherein ring A is a monocyclic 5 to 7 membered saturated heterocyclecontaining one heteroatom selected from N, O or S, said heteroatom notbeing positioned in alpha position of the double bond, wherein ring A isoptionally being substituted with cyano, C₁₋₄alkyl, hydroxyC₁₋₄alkyl,(C₁₋₄alkyl)₂N—C₁₋₄alkyl, (haloC₁₋₄alkyl)NH—C₁₋₄alkyl,C₁₋₄alkoxyC₁₋₄alkyl, —C(═O)—NH₂, —C(═O)—NH(C₁₋₄alkyl),—C(═O)—N(C₁₋₄alkyl)₂;

R^(3c) represents hydrogen, hydroxyl, C₁₋₆alkoxy, R⁹, —NR¹⁰R¹¹,—C(═O)—NR¹⁴R¹⁵, cyano, —C(═O)—C₁₋₆alkyl or —CH(OH)—C₁₋₆alkyl;

R³ represents hydroxyl, C₁₋₆alkoxy, hydroxyC₁₋₆alkoxy, C₁₋₆alkoxysubstituted with —NR¹⁰R¹¹, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,haloC₁₋₆alkyl optionally substituted with hydroxyC₁₋₆alkyl optionallysubstituted with —O—C(═O)—C₁₋₆alkyl, hydroxyC₂₋₆alkenyl,hydroxyC₂₋₆alkynyl, hydroxyhaloC₁₋₆alkyl, cyanoC₁₋₆alkyl, substitutedwith carboxyl, C₁₋₆alkyl substituted with —C(═O)—C₁₋₆alkyl, C₁₋₆alkylsubstituted with —C(═O)—O—C₁₋₆alkyl, C₁₋₆alkyl substituted withC₁₋₆alkoxyC₁₋₆alkyl-O—C(═O)—, C₁₋₆alkyl substituted withC₁₋₆alkoxyC₁₋₆alkyl-C(═O)—, C₁₋₆alkyl substituted withC₁₋₆alkoxyC₁₋₆alkyl wherein each C₁₋₆alkyl may optionally be substitutedwith one or two hydroxyl groups or with —O—C(═O)—C₁₋₆alkyl, C₂₋₆alkenylsubstituted with C₁₋₆alkoxy, C₂₋₆alkynyl substituted with C₁₋₆alkoxy,C₁₋₆alkyl substituted with R⁹ and optionally substituted with—O—C(═O)—C₁₋₆alkyl, C₁₋₆alkyl substituted with —C(═O)—R⁹, C₁₋₆alkylsubstituted with hydroxyl and R⁹, C₂₋₆alkenyl substituted with R⁹,C₂₋₆alkynyl substituted with R⁹, C₁₋₆alkyl substituted with —NR¹⁰R¹¹,C₂₋₆alkenyl substituted with —NR¹⁰R¹¹, C₂₋₆alkynyl substituted with—NR¹⁰R¹¹, C₁₋₆alkyl substituted with hydroxyl and —NR¹⁰R¹¹, C₁₋₆alkylsubstituted with one or two halogens and —NR¹⁶R¹¹,—C₁₋₆alkyl-C(R¹²)═N—O—R¹², C₁₋₆alkyl substituted with —C(═O)—NR¹⁰R¹¹,substituted with —O—C(═O)—NR¹⁰R¹¹, —S(═O)₂—C₁₋₆alkyl,—S(═O)₂-haloC₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with —S(═O)₂-haloC₁₋₆alkyl,C₁₋₆alkyl substituted with —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with—NR¹²—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with—NH—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with—NR¹²—S(═O)₂—NR¹⁴R¹⁵, R¹³, C₁₋₆alkyl substituted with —P(═O)(OH)₂ orC₁₋₆alkyl substituted with —P(═O)(OC₁₋₆alkyl)₂;

R⁴ and R⁵ each independently represent hydrogen, C₁₋₆alkyl, C₁₋₆alkylsubstituted with —NR¹⁴R¹⁵, hydroxyC₁₋₆alkyl, hydroxyhaloC₁₋₆alkyl,C₁₋₆alkoxyC₁₋₆alkyl wherein each C₁₋₆alkyl may optionally be substitutedwith one or two hydroxyl groups, —S(═O)₂—C₁₋₆alkyl,—S(═O)₂-haloC₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵, —C(═O)—NR¹⁴R¹⁵,—C(═O)—O—C₁₋₆alkyl, —C(═O)—R¹³, C₁₋₆alkyl substituted with—S(═O)₂—C₁₋₆alkyl, substituted with —S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkylsubstituted with —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with—NH—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with—NH—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with —NH—S(═O)₂—NR¹⁴R¹⁵,R¹³ or C₁₋₆alkyl substituted with R¹³;

R⁶ represents C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, phenyl, 4 to 7-memberedmonocyclic heterocyclyl containing at least one heteroatom selected fromN, O or S; said C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, phenyl, 4 to7-membered monocyclic heterocyclyl, optionally and each independentlybeing substituted by 1, 2, 3, 4 or 5 substituents, each substituentindependently being selected from cyano, C₁₋₆alkyl, cyanoC₁₋₆alkyl,hydroxyl, carboxyl, hydroxyC₁₋₆alkyl, halogen, haloC₁₋₆alkyl,hydroxyhaloC₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkoxyC₁₋₆alkyl, —NR¹⁴R¹⁵,—C(═O)—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with —NR¹⁴R¹⁵, C₁₋₆alkylsubstituted with —C(═O)—NR¹⁴R¹⁵, —S(═O)₂—C₁₋₆alkyl,—S(═O)₂-haloC₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with —S(═O)₂-haloC₁₋₆alkyl,C₁₋₆alkyl substituted with —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with—NH—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with—NH—S(═O)₂-haloC₁₋₆alkyl or C₁₋₆alkyl substituted with—NH—S(═O)₂—NR¹⁴R¹⁵;

R⁷ and R⁸ each independently represent hydrogen, C₁₋₆alkyl,hydroxyC₁₋₆alkyl, haloC₁₋₆alkyl, hydroxyhaloC₁₋₆alkyl orC₁₋₆alkoxyC₁₋₆alkyl;

R⁹ represents C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, phenyl, naphthyl, or 3to 12 membered monocyclic or bicyclic heterocyclyl containing at leastone heteroatom selected from N, O or S, said C₃₋₈cycloalkyl,C₃₋₈cycloalkenyl, phenyl, naphthyl, or 3 to 12 membered monocyclic orbicyclic heterocyclyl each optionally and each independently beingsubstituted with 1, 2, 3, 4 or 5 substituents, each substituentindependently being selected from ═O, C₁₋₄alkyl, hydroxyl, carboxyl,hydroxyC₁₋₄alkyl, cyano, cyanoC₁₋₄alkyl, C₁₋₄alkyl-O—C(═O)—, C₁₋₄alkylsubstituted with C₁₋₄alkyl-O—C(═O)—, C₁₋₄alkyl-C(═O)—,C₁₋₄alkoxyC₁₋₄alkyl wherein each C₁₋₄alkyl may optionally be substitutedwith one or two hydroxyl groups, halogen, haloC₁₋₄alkyl,hydroxyhaloC₁₋₄alkyl, —NR¹⁴R¹⁵, —C(═O)—NR¹⁴R¹⁵, C₁₋₄alkyl substitutedwith —NR¹⁴R¹⁵, C₁₋₄alkyl substituted with —C(═O)—NR¹⁴R¹⁵, C₁₋₄alkoxy,—S(═O)₂—C₁₋₄alkyl, —S(═O)₂-haloC₁₋₄alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₄alkylsubstituted with —S(═O)₂—NR¹⁴R¹⁵, C₁₋₄alkyl substituted with—NH—S(═O)₂—C₁₋₄alkyl, C₁₋₄alkyl substituted with—NH—S(═O)₂-haloC₁₋₄alkyl, C₁₋₄alkyl substituted with —NH—S(═O)₂—NR¹⁴R¹⁵,R¹³, —C(═O)—R¹³, C₁₋₄alkyl substituted with R¹³, phenyl optionallysubstituted with R¹⁶, phenylC₁₋₆alkyl wherein the phenyl is optionallysubstituted with R¹⁶, a 5 or 6-membered aromatic monocyclic heterocyclylcontaining at least one heteroatom selected from N, O or S wherein saidheterocyclyl is optionally substituted with R¹⁶;

or when two of the substituents of R⁹ are attached to the same atom,they may be taken together to form a 4 to 7-membered saturatedmonocyclic heterocyclyl containing at least one heteroatom selected fromN, O or S;

R¹⁰ and R¹¹ each independently represent hydrogen, carboxyl, C₁₋₆alkyl,cyanoC₁₋₆alkyl, C₁₋₆alkyl substituted with —NR¹⁴R¹⁵, C₁₋₆alkylsubstituted with —C(═O)—NR¹⁴R¹⁵, haloC₁₋₆alkyl, hydroxyC₁₋₆alkyl,hydroxyhaloC₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkoxyC₁₋₆alkyl wherein eachC₁₋₆alkyl may optionally be substituted with one or two hydroxyl groups,R⁶, C₁₋₆alkyl substituted with R⁶, —C(═O)—R⁶, —C(═O)—C₁₋₆alkyl,—C(═O)-hydroxyC₁₋₆alkyl, —C(═O)-haloC₁₋₆alkyl,—C(═O)-hydroxyhaloC₁₋₆alkyl, C₁₋₆alkyl substituted with —Si(CH₃)₃,—S(═O)₂—C₁₋₆alkyl, —S(═O)₂-haloC₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkylsubstituted with —S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with —S(═O)₂—NR¹⁴R¹⁵,C₁₋₆alkyl substituted with —NH—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substitutedwith —NH—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with carboxyl, orC₁₋₆alkyl substituted with —NH—S(═O)₂—NR¹⁴R¹⁵;

R¹² represents hydrogen or C₁₋₄alkyl optionally substituted withC₁₋₄alkoxy;

R¹³ represents C₃₋₈cycloalkyl or a saturated 4 to 6-membered monocyclicheterocyclyl containing at least one heteroatom selected from N, O or S,wherein said C₃₋₈cycloalkyl or monocyclic heterocyclyl is optionallysubstituted with 1, 2 or 3 substituents each independently selected fromhalogen, hydroxyl, C₁₋₆alkyl, haloC₁₋₆alkyl, ═O, cyano, C₁₋₆alkoxy, or—NR¹⁴R¹⁵;

R¹⁴ and R¹⁵ each independently represent hydrogen, or haloC₁₋₄alkyl, orC₁₋₄alkyl optionally substituted with a substituent selected fromhydroxyl, C₁₋₄alkoxy, amino or mono- or di(C₁₋₄alkyl)amino;

R¹⁶ represents hydroxyl, halogen, cyano, C₁₋₄alkyl, C₁₋₄alkoxy, —NR¹⁴R¹⁵or —C(═O)NR¹⁴R¹⁵;

n independently represents an integer equal to 0, 1, 2, 3 or 4;

the N-oxides thereof, the pharmaceutically acceptable salts thereof orthe solvates thereof.

WO2012/118492, WO2006/092430, WO2008/003702, WO01/68047, WO2005/007099,WO2004/098494, WO2009/141386, WO2004/030635, WO2008/141065,WO2011/026579, WO2011/028947, WO2007/003419, WO00/42026, WO2012/154760,WO2011/047129, WO2003/076416, WO2002/096873, WO2000/055153, EP548934,U.S. Pat. No. 4,166,117, WO2011/135376 and WO2012/073017 which eachdisclose a series of heterocyclyl derivatives.

DETAILED DESCRIPTION OF THE INVENTION

Unless the context indicates otherwise, references to formula (I) in allsections of this document (including the uses, methods and other aspectsof the invention) include references to all other sub-formula (e.g. Ia),sub-groups, preferences, embodiments and examples as defined herein.

The prefix “C_(x-y)” (where x and y are integers) as used herein refersto the number of carbon atoms in a given group. Thus, a C₁₋₆alkyl groupcontains from 1 to 6 carbon atoms, a C₃₋₆cycloalkyl group contains from3 to 6 carbon atoms, a C₁₋₄alkoxy group contains from 1 to 4 carbonatoms, and so on.

The term ‘halo’ or ‘halogen’ as used herein refers to a fluorine,chlorine, bromine or iodine atom.

The term ‘C₁₋₄alkyl’, or ‘C₁₋₆alkyl’ as used herein as a group or partof a group refers to a linear or branched saturated hydrocarbon groupcontaining from 1 to 4 or 1 to 6 carbon atoms. Examples of such groupsinclude methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or hexyl and thelike.

The term ‘C₂₋₄alkenyl’ or ‘C₂₋₆alkenyl’ as used herein as a group orpart of a group refers to a linear or branched hydrocarbon groupcontaining from 2 to 4 or 2 to 6 carbon atoms and containing a carboncarbon double bond.

The term ‘C₂₋₄alkynyl’ or ‘C₂₋₆alkynyl’ as used herein as a group orpart of a group refers to a linear or branched hydrocarbon group havingfrom 2 to 4 or 2 to 6 carbon atoms and containing a carbon carbon triplebond.

The term ‘C₁₋₄alkoxy’ or ‘C₁₋₆alkoxy’ as used herein as a group or partof a group refers to an —O—C₁₋₄alkyl group or an —O—C₁₋₆alkyl groupwherein C₁₋₄alkyl and C₁₋₆alkyl are as defined herein. Examples of suchgroups include methoxy, ethoxy, propoxy, butoxy, and the like.

The term ‘C₁₋₄alkoxyC₁₋₄alkyl’ or ‘C₁₋₆alkoxyC₁₋₆alkyl’ as used hereinas a group or part of a group refers to a C₁₋₄alkyl-O—C₁₋₄alkyl group ora C₁₋₆alkyl-O—C₁₋₆alkyl group wherein C₁₋₄alkyl and C₁₋₆alkyl are asdefined herein. Examples of such groups include methoxyethyl,ethoxyethyl, propoxymethyl, butoxypropyl, and the like.

The term ‘C₃₋₈cycloalkyl’ as used herein refers to a saturatedmonocyclic hydrocarbon ring of 3 to 8 carbon atoms. Examples of suchgroups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl or cyclooctyl and the like.

The term ‘C₃₋₈cycloalkenyl’ as used herein refers to a monocyclichydrocarbon ring of 3 to 8 carbon atoms having a carbon carbon doublebond.

The term ‘hydroxyC₁₋₄alkyl’ or ‘hydroxyC₁₋₆alkyl’ as used herein as agroup or part of a group refers to a C₁₋₄alkyl or C₁₋₆alkyl group asdefined herein wherein one or more than one hydrogen atom is replacedwith a hydroxyl group. The terms ‘hydroxyC₁₋₄alkyl’ or‘hydroxyC₁₋₆alkyl’ therefore include monohydroxyC₁₋₄alkyl,monohydroxyC₁₋₆alkyl and also polyhydroxyC₁₋₄alkyl andpolyhydroxyC₁₋₆alkyl. There may be one, two, three or more hydrogenatoms replaced with a hydroxyl group, so the hydroxyC₁₋₄alkyl orhydroxyC₁₋₆alkyl may have one, two, three or more hydroxyl groups.Examples of such groups include hydroxymethyl, hydroxyethyl,hydroxypropyl and the like.

The term ‘haloC₁₋₄alkyl’ or ‘haloC₁₋₆alkyl’ as used herein as a group orpart of a group refers to a C₁₋₄alkyl or C₁₋₆alkyl group as definedherein wherein one or more than one hydrogen atom is replaced with ahalogen. The term ‘haloC₁₋₄alkyl’ or ‘haloC₁₋₆alkyl’ therefore includemonohaloC₁₋₄alkyl, monohaloC₁₋₆alkyl and also polyhaloC₁₋₄alkyl andpolyhaloC₁₋₆alkyl. There may be one, two, three or more hydrogen atomsreplaced with a halogen, so the haloC₁₋₄alkyl or haloC₁₋₆alkyl may haveone, two, three or more halogens. Examples of such groups includefluoroethyl, fluoromethyl, trifluoromethyl or trifluoroethyl and thelike.

The term ‘hydroxyhaloC₁₋₄alkyl’ or ‘hydroxyhaloC₁₋₆alkyl’ as used hereinas a group or part of a group refers to a C₁₋₄alkyl or C₁₋₆alkyl groupas defined herein wherein one or more than one hydrogen atom is replacedwith a hydroxyl group and one or more than one hydrogen atom is replacedwith a halogen. The term ‘hydroxyhaloC₁₋₄alkyl’ or‘hydroxyhaloC₁₋₆alkyl’ therefore refers to a C₁₋₄alkyl or C₁₋₆alkylgroup wherein one, two, three or more hydrogen atoms are replaced with ahydroxyl group and one, two, three or more hydrogen atoms are replacedwith a halogen.

The term ‘hydroxyC₁₋₄alkoxy’ or ‘hydroxyC₁₋₆alkoxy’ as used herein as agroup or part of a group refers to an —O—C₁₋₄alkyl group or an—O—C₁₋₆alkyl group wherein the C₁₋₄alkyl and C₁₋₆alkyl group is asdefined above and one or more than one hydrogen atom of the C₁₋₄alkyl orC₁₋₆alkyl group is replaced with a hydroxyl group. The term‘hydroxyC₁₋₄alkoxy’ or ‘hydroxyC₁₋₆alkoxy’ therefore includemonohydroxyC₁₋₄alkoxy, monohydroxyC₁₋₆alkoxy and alsopolyhydroxyC₁₋₄alkoxy and polyhydroxyC₁₋₆alkoxy. There may be one, two,three or more hydrogen atoms replaced with a hydroxyl group so thehydroxyC₁₋₄alkoxy or hydroxyC₁₋₆alkoxy may have one, two, three or morehydroxyl groups. Examples of such groups include hydroxymethoxy,hydroxyethoxy, hydroxypropoxy and the like.

The term ‘haloC₁₋₄alkoxy’ or ‘haloC₁₋₆alkoxy’ as used herein as a groupor part of a group refers to a —O—C₁₋₄alkyl group or a —O—C₁₋₆ alkylgroup as defined herein wherein one or more than one hydrogen atom isreplaced with a halogen. The terms ‘haloC₁₋₄alkoxy’ or ‘haloC₁₋₆alkoxy’therefore include monohaloC₁₋₄alkoxy, monohaloC₁₋₆alkoxy and alsopolyhaloC₁₋₄alkoxy and polyhaloC₁₋₆alkoxy. There may be one, two, threeor more hydrogen atoms replaced with a halogen, so the haloC₁₋₄alkoxy orhaloC₁₋₆alkoxy may have one, two, three or more halogens. Examples ofsuch groups include fluoroethyloxy, difluoromethoxy or trifluoromethoxyand the like.

The term ‘hydroxyhaloC₁₋₄alkoxy’ as used herein as a group or part of agroup refers to an —O—C₁₋₄alkyl group wherein the C₁₋₄alkyl group is asdefined herein and wherein one or more than one hydrogen atom isreplaced with a hydroxyl group and one or more than one hydrogen atom isreplaced with a halogen. The term ‘hydroxyhaloC₁₋₄alkoxy’ thereforerefers to a —O—C₁₋₄alkyl group wherein one, two, three or more hydrogenatoms are replaced with a hydroxyl group and one, two, three or morehydrogen atoms are replaced with a halogen.

The term ‘haloC₁₋₄alkoxyC₁₋₄alkyl’ as used herein as a group or part ofa group refers to a C₁₋₄alkyl-O—C₁₋₄alkyl group wherein C₁₋₄alkyl is asdefined herein and wherein in one or both of the C₁₋₄alkyl groups one ormore than one hydrogen atom is replaced with a halogen. The term‘haloC₁₋₄ alkoxyC₁₋₄alkyl’ therefore refers to a C₁₋₄alkyl-O—C₁₋₄alkylgroup wherein in one or both of the C₁₋₄alkyl groups one, two, three ormore hydrogen atoms are replaced with a halogen and wherein C₁₋₄ alkylis as defined herein. Preferably, in one of the C₁₋₄alkyl groups one ormore than one hydrogen atom is replaced with a halogen. Preferably,haloC₁₋₄alkoxyC₁₋₄alkyl means C₁₋₄alkyl substituted with haloC₁₋₄alkoxy.

The term ‘hydroxyhaloC₁₋₄alkoxyC₁₋₄alkyl’ as used herein refers to aC₁₋₄alkyl-O—C₁₋₄alkyl group wherein C₁₋₄alkyl is as defined herein andwherein in one or both of the C₁₋₄alkyl groups one or more than onehydrogen atom is replaced with a hydroxyl group and one or more than onehydrogen atom is replaced with a halogen. The terms‘hydroxyhaloC₁₋₄alkoxyC₁₋₄alkyl’ therefore refers to aC₁₋₄alkyl-O—C₁₋₄alkyl group wherein in one or both of the C₁₋₄alkylgroups one, two, three or more hydrogen atoms are replaced with ahydroxyl group and one, two, three or more hydrogen atoms are replacedwith a halogen and wherein C₁₋₄alkyl is as defined herein.

The term ‘hydroxyC₂₋₆alkenyl’ as used herein refers to a C₂₋₆alkenylgroup wherein one or more than one hydrogen atom is replaced with ahydroxyl group and wherein C₂₋₆alkenyl is as defined herein.

The term ‘hydroxyC₂₋₆alkynyl’ as used herein refers to a C₂₋₆alkynylgroup wherein one or more than one hydrogen atom is replaced with ahydroxyl group and wherein C₂₋₆alkynyl is as defined herein.

The term ‘phenylC₁₋₆alkyl’ as used herein refers to a C₁₋₆alkyl group asdefined herein which is substituted with one phenyl group.

The term ‘cyanoC₁₋₄alkyl’ or ‘cyanoC₁₋₆alkyl’ as used herein refers to aC₁₋₄alkyl or C₁₋₆alkyl group as defined herein which is substituted withone cyano group.

The term “heterocyclyl” as used herein shall, unless the contextindicates otherwise, include both aromatic and non-aromatic ringsystems. Thus, for example, the term “heterocyclyl group” includeswithin its scope aromatic, non-aromatic, unsaturated, partiallysaturated and fully saturated heterocyclyl ring systems. In general,unless the context indicates otherwise, such groups may be monocyclic orbicyclic and may contain, for example, 3 to 12 ring members, moreusually 5 to 10 ring members. Reference to 4 to 7 ring members include4, 5, 6 or 7 atoms in the ring and reference to 4 to 6 ring membersinclude 4, 5, or 6 atoms in the ring. Examples of monocyclic groups aregroups containing 3, 4, 5, 6, 7 and 8 ring members, more usually 3 to 7,and preferably 5, 6 or 7 ring members, more preferably 5 or 6 ringmembers. Examples of bicyclic groups are those containing 8, 9, 10, 11and 12 ring members, and more usually 9 or 10 ring members. Wherereference is made herein to heterocyclyl groups, the heterocyclyl ringcan, unless the context indicates otherwise, be optionally substituted(i.e. unsubstituted or substituted) by one or more substituents asdiscussed herein.

The heterocyclyl groups can be heteroaryl groups having from 5 to 12ring members, more usually from 5 to 10 ring members. The term“heteroaryl” is used herein to denote a heterocyclyl group havingaromatic character. The term “heteroaryl” embraces polycyclic (e.g.bicyclic) ring systems wherein one or more rings are non-aromatic,provided that at least one ring is aromatic. In such polycyclic systems,the group may be attached by the aromatic ring, or by a non-aromaticring.

Examples of heteroaryl groups are monocyclic and bicyclic groupscontaining from five to twelve ring members, and more usually from fiveto ten ring members. The heteroaryl group can be, for example, a fivemembered or six membered monocyclic ring or a bicyclic structure formedfrom fused five and six membered rings or two fused six membered rings,or two fused five membered rings. Each ring may contain up to about fiveheteroatoms typically selected from nitrogen, sulphur and oxygen.Typically the heteroaryl ring will contain up to 4 heteroatoms, moretypically up to 3 heteroatoms, more usually up to 2, for example asingle heteroatom. In one embodiment, the heteroaryl ring contains atleast one ring nitrogen atom. The nitrogen atoms in the heteroaryl ringscan be basic, as in the case of an imidazole or pyridine, or essentiallynon-basic as in the case of an indole or pyrrole nitrogen. In generalthe number of basic nitrogen atoms present in the heteroaryl group,including any amino group substituents of the ring, will be less thanfive.

Examples of five membered heteroaryl groups include but are not limitedto pyrrole, furan, thiophene, imidazole, furazan, oxazole, oxadiazole,oxatriazole, isoxazole, thiazole, thiadiazole, isothiazole, pyrazole,triazole and tetrazole groups.

Examples of six membered heteroaryl groups include but are not limitedto pyridine, pyrazine, pyridazine, pyrimidine and triazine.

A bicyclic heteroaryl group may be, for example, a group selected from:

-   -   a) a benzene ring fused to a 5- or 6-membered ring containing 1,        2 or 3 ring heteroatoms;    -   b) a pyridine ring fused to a 5- or 6-membered ring containing        0, 1, 2 or 3 ring heteroatoms;    -   c) a pyrimidine ring fused to a 5- or 6-membered ring containing        0, 1 or 2 ring heteroatoms;    -   d) a pyrrole ring fused to a 5- or 6-membered ring containing 0,        1, 2 or 3 ring heteroatoms;    -   e) a pyrazole ring fused to a 5- or 6-membered ring containing        0, 1 or 2 ring heteroatoms;    -   f) an imidazole ring fused to a 5- or 6-membered ring containing        0, 1 or 2 ring heteroatoms;    -   g) an oxazole ring fused to a 5- or 6-membered ring containing        0, 1 or 2 ring heteroatoms;    -   h) an isoxazole ring fused to a 5- or 6-membered ring containing        0, 1 or 2 ring heteroatoms;    -   i) a thiazole ring fused to a 5- or 6-membered ring containing        0, 1 or 2 ring heteroatoms;    -   j) an isothiazole ring fused to a 5- or 6-membered ring        containing 0, 1 or 2 ring heteroatoms;    -   k) a thiophene ring fused to a 5- or 6-membered ring containing        0, 1, 2 or 3 ring heteroatoms;    -   l) a furan ring fused to a 5- or 6-membered ring containing 0,        1, 2 or 3 ring heteroatoms;    -   m) a cyclohexyl ring fused to a 5- or 6-membered ring containing        1, 2 or 3 ring heteroatoms; and    -   n) a cyclopentyl ring fused to a 5- or 6-membered ring        containing 1, 2 or 3 ring heteroatoms.

Particular examples of bicyclic heteroaryl groups containing a fivemembered ring fused to another five membered ring include but are notlimited to imidazothiazole (e.g. imidazo[2,1-b]thiazole) andimidazoimidazole (e.g. imidazo[1,2-a]imidazole).

Particular examples of bicyclic heteroaryl groups containing a sixmembered ring fused to a five membered ring include but are not limitedto benzofuran, benzothiophene, benzimidazole, benzoxazole,isobenzoxazole, benzisoxazole, benzthiazole, benzisothiazole,isobenzofuran, indole, isoindole, indolizine, indoline, isoindoline,purine (e.g., adenine, guanine), indazole, pyrazolopyrimidine (e.g.pyrazolo[1,5-a]pyrimidine), triazolopyrimidine (e.g.[1,2,4]triazolo[1,5-a]pyrimidine), benzodioxole, imidazopyridine andpyrazolopyridine (e.g. pyrazolo[1,5-a]pyridine) groups.

Particular examples of bicyclic heteroaryl groups containing two fusedsix membered rings include but are not limited to quinoline,isoquinoline, chroman, thiochroman, chromene, isochromene, chroman,isochroman, benzodioxan, quinolizine, benzoxazine, benzodiazine,pyridopyridine, quinoxaline, quinazoline, cinnoline, phthalazine,naphthyridine and pteridine groups.

Examples of polycyclic heteroaryl groups containing an aromatic ring anda non-aromatic ring include, tetrahydroisoquinoline,tetrahydroquinoline, dihydrobenzthiene, dihydrobenzfuran,2,3-dihydro-benzo[1,4]dioxine, benzo[1,3]dioxole,4,5,6,7-tetrahydrobenzofuran, tetrahydrotriazolopyrazine (e.g.5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine), indoline and indanegroups.

A nitrogen-containing heteroaryl ring must contain at least one ringnitrogen atom. Each ring may, in addition, contain up to about fourother heteroatoms typically selected from nitrogen, sulphur and oxygen.Typically the heteroaryl ring will contain up to 3 heteroatoms, forexample 1, 2 or 3, more usually up to 2 nitrogens, for example a singlenitrogen. The nitrogen atoms in the heteroaryl rings can be basic, as inthe case of an imidazole or pyridine, or essentially non-basic as in thecase of an indole or pyrrole nitrogen. In general the number of basicnitrogen atoms present in the heteroaryl group, including any aminogroup substituents of the ring, will be less than five.

Examples of nitrogen-containing heteroaryl groups include, but are notlimited to, pyridyl, pyrrolyl, imidazolyl, oxazolyl, oxadiazolyl,thiadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl,furazanyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl,triazolyl (e.g., 1,2,3-triazolyl, 1,2,4-triazolyl), tetrazolyl,quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzisoxazole,benzthiazolyl and benzisothiazole, indolyl, 3H-indolyl, isoindolyl,indolizinyl, isoindolinyl, purinyl (e.g., adenine [6-aminopurine],guanine [2-amino-6-hydroxypurine]), indazolyl, quinolizinyl,benzoxazinyl, benzodiazinyl, pyridopyridinyl, quinoxalinyl,quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl and pteridinyl.

Examples of nitrogen-containing polycyclic heteroaryl groups containingan aromatic ring and a non-aromatic ring includetetrahydroisoquinolinyl, tetrahydroquinolinyl, and indolinyl.

The term ‘non-aromatic group’, ‘non-aromatic ring system’ or‘non-aromatic ring’ embraces, unless the context indicates otherwise,unsaturated ring systems without aromatic character, partially saturatedand fully saturated heterocyclyl ring systems. The terms “unsaturated”and “partially saturated” refer to rings wherein the ring structure(s)contains atoms sharing more than one valence bond i.e. the ring containsat least one multiple bond e.g. a C═C, C≡C or N═C bond. The term “fullysaturated” refers to rings where there are no multiple bonds betweenring atoms. Saturated heterocyclyl groups include piperidine,morpholine, thiomorpholine, piperazine. Partially saturated heterocyclylgroups include pyrazolines, for example 2-pyrazoline and 3-pyrazoline.

Examples of non-aromatic heterocyclyl groups are groups having from 3 to12 ring members, more usually 5 to 10 ring members. Such groups can bemonocyclic or bicyclic, for example, and typically have from 1 to 5heteroatom ring members (more usually 1, 2, 3 or 4 heteroatom ringmembers), usually selected from nitrogen, oxygen and sulphur. Theheterocyclyl groups can contain, for example, cyclic ether moieties(e.g. as in tetrahydrofuran and dioxane), cyclic thioether moieties(e.g. as in tetrahydrothiophene and dithiane), cyclic amine moieties(e.g. as in pyrrolidine), cyclic amide moieties (e.g. as inpyrrolidone), cyclic thioamides, cyclic thioesters, cyclic ureas (e.g.as in imidazolidin-2-one) cyclic ester moieties (e.g. as inbutyrolactone), cyclic sulphones (e.g. as in sulpholane and sulpholene),cyclic sulphoxides, cyclic sulphonamides and combinations thereof (e.g.thiomorpholine).

Particular examples include morpholine, piperidine (e.g. 1-piperidinyl,2-piperidinyl, 3-piperidinyl and 4-piperidinyl), piperidone, pyrrolidine(e.g. 1-pyrrolidinyl, 2-pyrrolidinyl and 3-pyrrolidinyl), pyrrolidone,azetidine, pyran (2H-pyran or 4H-pyran), dihydrothiophene, dihydropyran,dihydrofuran, dihydrothiazole, tetrahydrofuran, tetrahydrothiophene,dioxane, tetrahydropyran (e.g. 4-tetrahydro pyranyl), imidazoline,imidazolidinone, oxazoline, thiazoline, 2-pyrazoline, pyrazolidine,piperazone, piperazine, and N-alkyl piperazines such as N-methylpiperazine. In general, preferred non-aromatic heterocyclyl groupsinclude saturated groups such as piperidine, pyrrolidine, azetidine,morpholine, piperazine and N-alkyl piperazines.

In a nitrogen-containing non-aromatic heterocyclyl ring the ring mustcontain at least one ring nitrogen atom. The heterocylic groups cancontain, for example cyclic amine moieties (e.g. as in pyrrolidine),cyclic amides (such as a pyrrolidinone, piperidone or caprolactam),cyclic sulphonamides (such as an isothiazolidine 1,1-dioxide,[1,2]thiazinane 1,1-dioxide or [1,2]thiazepane 1,1-dioxide) andcombinations thereof. Particular examples of nitrogen-containingnon-aromatic heterocyclyl groups include aziridine, morpholine,thiomorpholine, piperidine (e.g. 1-piperidinyl, 2-piperidinyl,3-piperidinyl and 4-piperidinyl), pyrrolidine (e.g. 1-pyrrolidinyl,2-pyrrolidinyl and 3-pyrrolidinyl), pyrrolidone, dihydrothiazole,imidazoline, imidazolidinone, oxazoline, thiazoline,6H-1,2,5-thiadiazine, 2-pyrazoline, 3-pyrazoline, pyrazolidine,piperazine, and N-alkyl piperazines such as N-methyl piperazine.

The heterocyclyl groups can be polycyclic fused ring systems or bridgedring systems such as the oxa- and aza analogues of bicycloalkanes,tricycloalkanes (e.g. adamantane and oxa-adamantane). For an explanationof the distinction between fused and bridged ring systems, see AdvancedOrganic Chemistry, by Jerry March, 4th Edition, Wiley Interscience,pages 131-133, 1992.

The heterocyclyl groups can each be unsubstituted or substituted by oneor more substituent groups. For example, heterocyclyl groups can beunsubstituted or substituted by 1, 2, 3 or 4 substituents. Where theheterocyclyl group is monocyclic or bicyclic, typically it isunsubstituted or has 1, 2 or 3 substituents.

The term “carbocyclyl” as used herein shall, unless the contextindicates otherwise, include both aromatic and non-aromatic ringsystems. Thus, for example, the term “carbocyclyl group” includes withinits scope aromatic, non-aromatic, unsaturated, partially saturated andfully saturated carbocyclyl ring systems. In general, unless the contextindicates otherwise, such groups may be monocyclic or bicyclic and maycontain, for example, 3 to 12 ring members, more usually 5 to 10 ringmembers. Reference to 4 to 7 ring members include 4, 5, 6 or 7 atoms inthe ring and reference to 4 to 6 ring members include 4, 5, or 6 atomsin the ring. Examples of monocyclic groups are groups containing 3, 4,5, 6, 7 and 8 ring members, more usually 3 to 7, and preferably 5, 6 or7 ring members, more preferably 5 or 6 ring members. Examples ofbicyclic groups are those containing 8, 9, 10, 11 and 12 ring members,and more usually 9 or 10 ring members. Where reference is made herein tocarbocyclyl groups, the carbocyclyl ring can, unless the contextindicates otherwise, be optionally substituted (i.e. unsubstituted orsubstituted) by one or more substituents as discussed herein.

The term ‘carbocyclyl’ comprises aryl, C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl.

The term ‘aryl’ as used herein refers to carbocyclyl aromatic groupsincluding phenyl, naphthyl, indenyl, and tetrahydronaphthyl groups.

Whenever used hereinbefore or hereinafter that substituents can beselected each independently out of a list of numerous definitions, allpossible combinations are intended which are chemically possible.Whenever used hereinbefore or hereinafter that a particular substituentis further substituted with two or more groups, such as for examplehydroxyhaloC₁₋₄alkyl, hydroxyhaloC₁₋₄alkoxy, all possible combinationsare intended which are chemically possible.

In one embodiment, D represents an aromatic ring.

In one embodiment, D represents a 5 to 12 ring membered monocyclic orbicyclic carbocyclyl or a 5 to 12 ring membered monocyclic or bicyclicheterocyclyl containing at least one heteroatom selected from N, O or S,wherein said carbocyclyl and heterocyclyl may each be optionallysubstituted by one or more (e.g. 1, 2 or 3) R¹ groups.

In one embodiment, D represents an aromatic 3 to 12, in particular anaromatic 5 to 12, ring membered monocyclic or bicyclic carbocyclyl or anaromatic 3 to 12, in particular an aromatic 5 to 12, ring memberedmonocyclic or bicyclic heterocyclyl containing at least one heteroatomselected from N, O or S, wherein said carbocyclyl and heterocyclyl mayeach be optionally substituted by one or more (e.g. 1, 2 or 3) R¹groups.

In one embodiment, D represents an aromatic 3 to 12 (e.g. 5 to 10) ringmembered monocyclic or bicyclic carbocyclyl, wherein said carbocyclylmay be optionally substituted by one or more (e.g. 1, 2 or 3) R¹ groups.

In one embodiment, D represents phenyl or naphthyl, wherein said phenylor naphthyl may each be optionally substituted by one or more (e.g. 1, 2or 3) R¹ groups.

In one embodiment, D represents a 5 to 12 ring membered monocyclic orbicyclic heterocyclyl containing at least one heteroatom selected fromN, O or S, wherein said heterocyclyl may each be optionally substitutedby one or more (e.g. 1, 2 or 3) R¹ groups.

In one embodiment, D represents an aromatic 5 to 12 ring memberedmonocyclic heterocyclyl containing at least one heteroatom selected fromN, O or S, wherein said heterocyclyl group may each be optionallysubstituted by one or more (e.g. 1, 2 or 3) R¹ groups.

In one embodiment, D represents a 5 or 6 ring membered monocyclicheterocyclyl containing at least one heteroatom selected from N, O or S,wherein said heterocyclyl may each be optionally substituted by one ormore (e.g. 1, 2 or 3) R¹ groups.

In one embodiment, D represents an aromatic 5 or 6 ring memberedmonocyclic heterocyclyl containing at least one heteroatom selected fromN, O or S, wherein said heterocyclyl may each be optionally substitutedby one or more (e.g. 1, 2 or 3) R¹ groups.

In one embodiment, D represents a 5 ring membered monocyclicheterocyclyl containing at least one heteroatom selected from N, O or S,wherein said heterocyclyl may each be optionally substituted by one ormore (e.g. 1, 2 or 3) R¹ groups.

In one embodiment, D represents a 5 ring membered monocyclic aromaticheterocyclyl containing at least one heteroatom selected from N, O or S,wherein said heterocyclyl may each be optionally substituted by one ormore (e.g. 1, 2 or 3) R¹ groups.

In one embodiment, D represents pyrazolyl (e.g. pyrazol-4yl), whereinsaid pyrazolyl may each be optionally substituted by one or more (e.g.1, 2 or 3) R¹ groups.

In one embodiment, D represents a 6 ring membered monocyclicheterocyclyl containing at least one heteroatom selected from N, O or S,wherein said heterocyclyl may each be optionally substituted by one ormore (e.g. 1, 2 or 3) R¹ groups.

In one embodiment, D represents a 6 ring membered monocyclic aromaticheterocyclyl containing at least one heteroatom selected from N, O or S,wherein said heterocyclyl may each be optionally substituted by one ormore (e.g. 1, 2 or 3) R¹ groups.

In one embodiment, D represents a 12 ring membered bicyclic heterocyclylcontaining at least one heteroatom selected from N, O or S, wherein saidheterocyclyl may each be optionally substituted by one or more (e.g. 1,2 or 3) R¹ groups.

In one embodiment, D represents a 12 ring membered bicyclic aromaticheterocyclyl containing at least one heteroatom selected from N, O or S,wherein said heterocyclyl may each be optionally substituted by one ormore (e.g. 1, 2 or 3) R¹ groups.

In one embodiment D represents

wherein R¹ represents hydrogen, C₁₋₆alkyl, C₂₋₄alkenyl,hydroxyC₁₋₆alkyl, haloC₁₋₆alkyl, hydroxyhaloC₁₋₆alkyl, cyanoC₁₋₄alkyl,C₁₋₆alkoxyC₁₋₆alkyl wherein each C₁₋₆alkyl may optionally be substitutedwith one or two hydroxyl groups, C₁₋₆alkyl substituted with —NR⁴R⁵,C₁₋₆alkyl substituted with —C(═O)—NR⁴R⁵, —S(═O)₂—C₁₋₆alkyl,—S(═O)₂-haloC₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with —S(═O)₂-haloC₁₋₆alkyl,C₁₋₆alkyl substituted with —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with—NH—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with—NH—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with—NR¹²—S(═O)₂—NR¹⁴R¹⁵, R⁶, C₁₋₆alkyl substituted with R⁶, C₁₋₆alkylsubstituted with —C(═O)—R⁶, hydroxyC₁₋₆alkyl substituted with R⁶,C₁₋₆alkyl substituted with —Si(CH₃)₃, C₁₋₆alkyl substituted with—P(═O)(OH)₂ or C₁₋₆alkyl substituted with —P(═O)(OC₁₋₆alkyl)₂; and eachR^(1a) is independently selected from hydrogen, C₁₋₄alkyl,hydroxyC₁₋₄alkyl, C₁₋₄alkyl substituted with amino or mono- ordi(C₁₋₄alkyl)amino or —NH(C₃₋₈cycloalkyl), cyanoC₁₋₄alkyl,C₁₋₄alkoxyC₁₋₄alkyl, and C₁₋₄alkyl substituted with one or more fluoroatoms. In one embodiment R^(1a) is independently selected from hydrogenand C₁₋₄alkyl. In one embodiment R^(1a) is hydrogen.

In one embodiment, D represents

wherein R¹ represents hydrogen, C₁₋₆alkyl, C₂₋₄alkenyl,hydroxyC₁₋₆alkyl, hydroxyhaloC₁₋₆alkyl, C₁₋₆alkoxyC₁₋₆alkyl wherein eachC₁₋₆alkyl may optionally be substituted with one or two hydroxyl groups,C₁₋₆alkyl substituted with —NR⁴R⁵, C₁₋₆alkyl substituted with—C(═O)—NR⁴R⁵, —S(═O)₂—C₁₋₆alkyl, —S(═O)₂-haloC₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵,C₁₋₆alkyl substituted with —S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with —S(═O)₂—NR¹⁴R¹⁵,C₁₋₆alkyl substituted with —NH—S(═O)₂—C₁₋₆alkyl, substituted with—NH—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with—NR¹²—S(═O)₂—NR¹⁴R¹⁵, R⁶, C₁₋₆alkyl substituted with R⁶, C₁₋₆alkylsubstituted with —C(═O)—R⁶, hydroxyC₁₋₆alkyl substituted with R⁶,C₁₋₆alkyl substituted with —Si(CH₃)₃, substituted with —P(═O)(OH)₂ orC₁₋₆alkyl substituted with —P(═O)(OC₁₋₆alkyl)₂.

In one embodiment, D is other than pyrazolyl, in particular D ispyridinyl, phenyl, pyrolyl, imidazolyl, triazolyl, pyrolopyridinyl,1,3-benzodioxolyl, indolyl, thiazolyl, tetrazolyl, oxazolyl,pyrimidinyl, thiadiazolyl, oxadiazolyl, said rings being optionallysubstituted. Said optional substituents may represent halo, cyano,C₁₋₆alkyl, C₁₋₆alkoxy, —C(═O)—O—C₁₋₆alkyl, hydroxyC₁₋₆alkyl, —NR⁴R⁵,C₁₋₆alkyl substituted with —O—C(═O)—C₁₋₆alkyl, C₁₋₆alkyl substitutedwith —NR⁴R⁵, —C(═O)—NR⁴R⁵, —C(═O)—C₁₋₆alkyl-NR⁴R⁵, R⁶, C₁₋₆alkylsubstituted with R⁶.

In one embodiment, D is optionally substituted 4-pyrazolyl. In oneembodiment, D is 4-pyrazolyl substituted at the 1 position withC₁₋₆alkyl for example methyl.

In one embodiment, D is 1-pyrazolyl or 2-pyrazolyl, both may optionallybe substituted.

In one embodiment, D is optionally substituted pyrazolyl.

In one embodiment, D is other than pyrazolyl, in particular D ispyridinyl, phenyl, pyrolyl, imidazolyl, triazolyl, pyrolopyridinyl,1,3-benzodioxolyl, indolyl, thiazolyl, tetrazolyl, oxazolyl,pyrimidinyl, said rings being optionally substituted.

In one embodiment, D is optionally substituted phenyl.

In one embodiment, D is phenyl.

In one embodiment, D is phenyl or optionally substituted pyrazolyl.

In one embodiment, D is a 3 to 12 ring membered monocyclic or bicycliccarbocyclyl or a 3 to 12 ring membered monocyclic or bicyclicheterocyclyl containing at least one heteroatom selected from N, O or S,wherein said carbocyclyl and heterocyclyl is substituted by one or more(e.g. 1, 2 or 3) R¹ groups.

In one embodiment, D is substituted phenyl or substituted pyrazolyl.

In one embodiment, D represents a 3 to 12 ring membered monocyclic orbicyclic carbocyclyl or a 3 to 12 ring membered monocyclic or bicyclicheterocyclyl containing at least one heteroatom selected from N, O or S,wherein said carbocyclyl and heterocyclyl is substituted by one or more(e.g. 1, 2 or 3) R¹ groups;

R¹ represents C₁₋₄alkyl.

In one embodiment, D is pyrazolyl or phenyl, each optionally substitutedwith C₁₋₄alkyl; in particular D is pyrazolyl optionally substituted withC₁₋₄alkyl.

In one embodiment, D is pyrazolyl or phenyl, each optionally substitutedwith C₁₋₄alkyl; W is —N(R³)— or —C(═O)—; R³ is C₁₋₆alkyl substitutedwith R⁹, or C₁₋₆alkyl substituted with —NR¹⁰R¹¹.

In one embodiment, D is pyrazolyl or phenyl, each optionally substitutedwith C₁₋₄alkyl; W is —N(R³)—; R³ is C₁₋₆alkyl substituted with R⁹, orC₁₋₆alkyl substituted with —NR¹⁰R¹¹.

In one embodiment, D is pyrazolyl optionally substituted with C₁₋₄alkyl;W is —N(R³)—; R³ is C₁₋₆alkyl substituted with R⁹, or C₁₋₆alkylsubstituted with —NR¹⁰R¹¹.

In one embodiment, D is pyrazolyl substituted with C₁₋₄alkyl; W is—N(R³)—; R³ is C₁₋₆alkyl substituted with R⁹; R⁹ is imidazolyl.

In one embodiment, D is pyrazolyl substituted with C₁₋₄alkyl; W is—N(R³)—.

In one embodiment, D represents a 3 to 12 ring membered monocyclic orbicyclic heterocyclyl containing at least one heteroatom selected fromN, O or S, wherein said carbocyclyl and heterocyclyl may each beoptionally substituted by one or more (e.g. 1, 2 or 3) R¹ groups; W is—N(R³)—.

In one embodiment R¹ represents hydrogen, C₁₋₆alkyl, C₂₋₄alkenyl,hydroxyC₁₋₆alkyl, haloC₁₋₆alkyl, hydroxyhaloC₁₋₆alkyl, cyanoC₁₋₄alkyl,C₁₋₆alkoxyC₁₋₆alkyl wherein each C₁₋₆alkyl may optionally be substitutedwith one or two hydroxyl groups, C₁₋₆alkyl substituted with —NR⁴R⁵,C₁₋₆alkyl substituted with —C(═O)—NR⁴R⁵, —S(═O)₂—C₁₋₆alkyl,—S(═O)₂-haloC₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with —S(═O)₂-haloC₁₋₆alkyl,C₁₋₆alkyl substituted with —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with—NH—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with—NH—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with—NR¹²—S(═O)₂—NR¹⁴R¹⁵, R⁶, C₁₋₆alkyl substituted with R⁶, C₁₋₆alkylsubstituted with —C(═O)—R⁶, hydroxyC₁₋₆alkyl substituted with R⁶,C₁₋₆alkyl substituted with —Si(CH₃)₃, C₁₋₆alkyl substituted with—P(═O)(OH)₂ or C₁₋₆alkyl substituted with —P(═O)(OC₁₋₆alkyl)₂.

In one embodiment R¹ represents hydrogen, C₁₋₆alkyl, C₂₋₄alkenyl,hydroxyC₁₋₆alkyl, haloC₁₋₆alkyl, C₁₋₆alkoxyC₁₋₆alkyl wherein eachC₁₋₆alkyl may optionally be substituted with one or two hydroxyl groups,C₁₋₆alkyl substituted with —NR⁴R⁵, C₁₋₆alkyl substituted with—C(═O)—NR⁴R⁵, —S(═O)₂—C₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substitutedwith —S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with —NH—S(═O)₂—C₁₋₆alkyl,R⁶, C₁₋₆alkyl substituted with R⁶, C₁₋₆alkyl substituted with —C(═O)—R⁶,hydroxyC₁₋₆alkyl substituted with R⁶, or C₁₋₆alkyl substituted with—Si(CH₃)₃.

In one embodiment R¹ represents hydrogen, halo, cyano, C₁₋₆alkyl,C₁₋₆alkoxy, —C(═O)—O—C₁₋₆alkyl, C₂₋₄alkenyl, hydroxyC₁₋₆alkyl,haloC₁₋₆alkyl, hydroxyhaloC₁₋₆alkyl, cyanoC₁₋₄alkyl, C₁₋₆alkoxyC₁₋₆alkylwherein each C₁₋₆alkyl may optionally be substituted with one or twohydroxyl groups, C₁₋₆alkyl substituted with —O—C(═O)—C₁₋₆alkyl,C₁₋₆alkyl substituted with —NR⁴R⁵, —C(═O)—C₁₋₆alkyl-NR⁴R⁵, C₁₋₆alkylsubstituted with —C(═O)—NR⁴R⁵, —S(═O)₂—C₁₋₆alkyl, —S(═O)₂-haloC₁₋₆alkyl,—S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with —S(═O)₂—C₁₋₆alkyl, C₁₋₆alkylsubstituted with —S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with—S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with —NH—S(═O)₂—C₁₋₆alkyl,C₁₋₆alkyl substituted with —NH—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkylsubstituted with —NR¹²—S(═O)₂—NR¹⁴R¹⁵, R⁶, C₁₋₆alkyl substituted withR⁶, —C(═O)—R⁶, C₁₋₆alkyl substituted with —C(═O)—R⁶, hydroxyC₁₋₆alkylsubstituted with R⁶, C₁₋₆alkyl substituted with —Si(CH₃)₃, C₁₋₆alkylsubstituted with —P(═O)(OH)₂ or C₁₋₆alkyl substituted with—P(═O)(OC₁₋₆alkyl)₂.

In one embodiment R¹ represents hydrogen.

In one embodiment R¹ represents C₁₋₆alkyl. In one embodiment R¹represents methyl.

In one embodiment, R¹ is not C₁₋₆alkyl substituted with R⁶.

In one embodiment R¹ represents hydrogen, halo, cyano, C₁₋₆alkyl,C₁₋₆alkoxy, —C(═O)—O—C₁₋₆alkyl, C₂₋₄alkenyl, hydroxyC₁₋₆alkyl,haloC₁₋₆alkyl, hydroxyhaloC₁₋₆alkyl, cyanoC₁₋₄alkyl, C₁₋₆alkoxyC₁₋₆alkylwherein each C₁₋₆alkyl may optionally be substituted with one or twohydroxyl groups, —NR⁴R⁵, C₁₋₆alkyl substituted with —O—C(═O)—C₁₋₆alkyl,C₁₋₆alkyl substituted with —NR⁴R⁵, —C(═O)—NR⁴R⁵, —C(═O)—C₁₋₆alkyl-NR⁴R⁵,C₁₋₆alkyl substituted with —C(═O)—NR⁴R⁵, —S(═O)₂—C₁₋₆alkyl,—S(═O)₂-haloC₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with —S(═O)₂-haloC₁₋₆alkyl,C₁₋₆alkyl substituted with —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with—NH—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with—NH—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with—NR¹²—S(═O)₂—NR¹⁴R¹⁵, R⁶, —C(═O)—R⁶, C₁₋₆alkyl substituted with—C(═O)—R⁶, hydroxyC₁₋₆alkyl substituted with R⁶, C₁₋₆alkyl substitutedwith —Si(CH₃)₃, C₁₋₆alkyl substituted with —P(═O)(OH)₂ or C₁₋₆alkylsubstituted with —P(═O)(OC₁₋₆alkyl)₂.

In one embodiment R¹ represents hydrogen, halo, cyano, C₁₋₆alkyl,C₁₋₆alkoxy, —C(═O)—O—C₁₋₆alkyl, C₂₋₄alkenyl, hydroxyC₁₋₆alkyl,haloC₁₋₆alkyl, hydroxyhaloC₁₋₆alkyl, cyanoC₁₋₄alkyl, C₁₋₆alkoxyC₁₋₆alkylwherein each C₁₋₆alkyl may optionally be substituted with one or twohydroxyl groups, C₁₋₆alkyl substituted with —O—C(═O)—C₁₋₆alkyl,C₁₋₆alkyl substituted with —NR⁴R⁵, —C(═O)—C₁₋₆alkyl-NR⁴R⁵, C₁₋₆alkylsubstituted with —C(═O)—NR⁴R⁵, —S(═O)₂—C₁₋₆alkyl, —S(═O)₂-haloC₁₋₆alkyl,—S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with —S(═O)₂—C₁₋₆alkyl, C₁₋₆alkylsubstituted with —S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with—S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with —NH—S(═O)₂—C₁₋₆alkyl,C₁₋₆alkyl substituted with —NH—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkylsubstituted with —NR¹²—S(═O)₂—NR¹⁴R¹⁵, R⁶, —C(═O)—R⁶, C₁₋₆alkylsubstituted with —C(═O)—R⁶, hydroxyC₁₋₆alkyl substituted with R⁶,C₁₋₆alkyl substituted with —Si(CH₃)₃, C₁₋₆alkyl substituted with—P(═O)(OH)₂ or C₁₋₆alkyl substituted with —P(═O)(OC₁₋₆alkyl)₂.

In one embodiment each R² is independently selected from hydroxyl,halogen, cyano, C₁₋₄alkyl, C₂₋₄alkenyl, C₁₋₄alkoxy, hydroxyC₁₋₄alkyl,hydroxyC₁₋₄alkoxy, haloC₁₋₄alkyl, haloC₁₋₄alkoxy, C₁₋₄alkoxyC₁₋₄alkyl,R¹³, C₁₋₄alkoxy substituted with R¹³, —C(═O)—R¹³, C₁₋₄alkyl substitutedwith NR⁷R⁸, C₁₋₄alkoxy substituted with NR⁷R⁸, —NR⁷R⁸ and —C(═O)—NR⁷R⁸;or when two R² groups are attached to adjacent carbon atoms they may betaken together to form a radical of formula —O—(C(R¹⁷)₂)_(p)—O— whereinR¹⁷ represents hydrogen or fluorine and p represents 1 or 2.

In one embodiment each R² is independently selected from hydroxyl,halogen, cyano, C₁₋₄alkyl, C₂₋₄alkenyl, C₁₋₄alkoxy, hydroxyC₁₋₄alkyl,hydroxyC₁₋₄alkoxy, haloC₁₋₄alkoxy, C₁₋₄alkoxyC₁₋₄alkyl, R¹³, C₁₋₄alkoxysubstituted with R¹³, —C(═O)—R¹³, C₁₋₄alkyl substituted with NR⁷R⁸,C₁₋₄alkoxy substituted with NR⁷R⁸, —NR⁷R⁸ or —C(═O)—NR⁷R⁸.

In one embodiment one or more R² represents C₁₋₄alkoxy, for exampleCH₃O—, or halo, for example fluoro.

In one embodiment one or more R² represents C₁₋₄alkoxy, for exampleCH₃O—.

In one embodiment n is equal to 0. In one embodiment n is equal to 1. Inone embodiment n is equal to 2. In one embodiment n is equal to 3. Inone embodiment n is equal to 4.

In one embodiment, n is equal to 1, 2, 3 or 4.

In one embodiment, n is equal to 1, 2, 3 or 4, in particular 4, and atleast one R² represents C₁₋₄alkyloxy, for example CH₃O—.

In one embodiment, n is equal to 2, 3 or 4.

In one embodiment, n is 4.

In one embodiment n is equal to 2 and one R² is present at the3-position and the other is present at the 5-position.

In one embodiment n is equal to 2 and one R² is present at the3-position and the other is present at the 5-position and each R²represents C₁₋₄alkoxy, for example each R² represents CH₃O—.

In one embodiment n is equal to 3 and one R² is present at the2-position, one R² is present at the 3-position and one R² is present atthe 5-position.

In one embodiment n is equal to 3 and one R² is present at the3-position and represents C₁₋₄alkoxy, for example CH₃O—; one R² ispresent at the 5-position and represents C₁₋₄alkoxy, for example CH₃O—;one R² is present at the 2-position and represents halogen, for examplefluoro.

In one embodiment n is equal to 4 and one R² is present at the2-position, one R² is present at the 3-position, one R² is present atthe 5-position and one R² is present at the 6-position.

In one embodiment n is equal to 4 and one R² is present at the3-position and represents C₁₋₄alkoxy, for example CH₃O—; one R² ispresent at the 5-position and represents C₁₋₄alkoxy, for example CH₃O—;one R² is present at the 2-position and represents halogen, for examplefluoro, and one R² is present at the 6-position and represents halogen,for example fluoro.

In one embodiment, R³ represents C₁₋₆alkyl, hydroxyC₁₋₆alkyl,hydroxyhaloC₁₋₆alkyl, hydroxyC₂₋₆alkynyl, haloC₁₋₆alkyl, haloC₁₋₆alkyloptionally substituted (e.g. substituted) with —O—C(═O)—C₁₋₆alkyl,C₁₋₆alkyl substituted with —C(═O)—C₁₋₆alkyl, C₁₋₆alkoxyC₁₋₆alkyl whereineach C₁₋₆alkyl may optionally be substituted with one or two hydroxylgroups, C₁₋₆alkoxyC₁₋₆alkyl wherein each C₁₋₆alkyl may optionally besubstituted with one or two hydroxyl groups or with —O—C(═O)—C₁₋₆alkyl,C₁₋₆alkyl substituted with R⁹, C₁₋₆alkyl substituted with —NR¹⁰R¹¹,C₁₋₆alkyl substituted with hydroxyl and —NR¹⁰R¹¹, C₁₋₆alkyl substitutedwith one or two halogens and —NR¹⁰R¹¹, C₁₋₆alkyl substituted with—C(═O)—O—C₁₋₆alkyl, C₁₋₆alkyl substituted with —C(═O)—NR¹⁰R¹¹, C₁₋₆alkylsubstituted with carboxyl, C₁₋₆alkyl substituted with —O—C(═O)—NR¹⁰R¹¹,C₁₋₆alkyl substituted with —NR¹²—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substitutedwith —NR¹²—S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with R⁹ and optionallysubstituted with —O—C(═O)—C₁₋₆alkyl, C₁₋₆alkyl substituted with hydroxyland R⁹, —C₁₋₆alkyl-C(R¹²)═N—O—R¹², —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkylsubstituted with —S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with—C(═O)—NR¹⁰R¹¹, C₁₋₆alkyl substituted with —C(═O)—R⁹, C₂₋₆alkenylsubstituted with R⁹, C₂₋₆alkynyl substituted with R⁹, hydroxyC₁₋₆alkoxy,C₂₋₆alkenyl, C₂₋₆alkynyl, R¹³, C₁₋₆alkyl substituted withC₁₋₆alkoxyC₁₋₆alkyl-C(═O)— or C₁₋₆alkyl substituted with—P(═O)(OC₁₋₆alkyl)₂.

In one embodiment, R³ represents C₁₋₆alkyl, hydroxyC₁₋₆alkyl,hydroxyhaloC₁₋₆alkyl, haloC₁₋₆alkyl optionally substituted (e.g.substituted) with —O—C(═O)—C₁₋₆alkyl, C₁₋₆alkyl substituted with—C(═O)—C₁₋₆alkyl, C₁₋₆alkoxyC₁₋₆alkyl wherein each C₁₋₆alkyl mayoptionally be substituted with one or two hydroxyl groups,C₁₋₆alkoxyC₁₋₆alkyl wherein each C₁₋₆alkyl may optionally be substitutedwith one or two hydroxyl groups or with —O—C(═O)—C₁₋₆alkyl, C₁₋₆alkylsubstituted with R⁹, C₁₋₆alkyl substituted with —NR¹⁰R¹¹, C₁₋₆alkylsubstituted with hydroxyl and —NR¹⁰R¹¹, C₁₋₆alkyl substituted with oneor two halogens and —NR¹⁰R¹¹, C₁₋₆alkyl substituted with—C(═O)—O—C₁₋₆alkyl, substituted with —C(═O)—NR¹⁰R¹¹, C₁₋₆alkylsubstituted with carboxyl, C₁₋₆alkyl substituted with —O—C(═O)—NR¹⁰R¹¹,C₁₋₆alkyl substituted with —NR¹²—S(═O)₂—C₁₋₆alkyl, substituted with—NR¹²—S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with R⁹ and optionallysubstituted with —O—C(═O)—C₁₋₆alkyl, C₁₋₆alkyl substituted with hydroxyland R⁹, —C₁₋₆alkyl-C(R¹²)═N—O—R¹², —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkylsubstituted with —S(═O)₂—C₁₋₆alkyl, substituted with —C(═O)—NR¹⁰R¹¹,C₁₋₆alkyl substituted with —C(═O)—R⁹, C₂₋₆alkenyl substituted with R⁹,hydroxyC₁₋₆alkoxy, C₂₋₆alkenyl, R¹³, C₁₋₆alkyl substituted withC₁₋₆alkoxyC₁₋₆alkyl-C(═O)— or C₁₋₆alkyl substituted with—P(═O)(OC₁₋₆alkyl)₂.

In one embodiment R³ represents C₁₋₆alkyl, hydroxyC₁₋₆alkyl,hydroxyhaloC₁₋₆alkyl, haloC₁₋₆alkyl, C₁₋₆alkyl substituted with—C(═O)—C₁₋₆alkyl, C₁₋₆alkoxyC₁₋₆alkyl wherein each C₁₋₆alkyl mayoptionally be substituted with one or two hydroxyl groups, C₁₋₆alkylsubstituted with R⁹, C₁₋₆alkyl substituted with —NR¹⁰R¹¹, C₁₋₆alkylsubstituted with hydroxyl and —NR¹⁰R¹¹, C₁₋₆alkyl substituted with oneor two halogens and —NR¹⁰R¹¹, C₁₋₆alkyl substituted with—C(═O)—O—C₁₋₆alkyl, C₁₋₆alkyl substituted with —C(═O)—NR¹⁰R¹¹, C₁₋₆alkylsubstituted with carboxyl, C₁₋₆alkyl substituted with —O—C(═O)—NR¹⁰R¹¹,substituted with —NR¹²—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with—NR¹²—S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with hydroxyl and R⁹,—C₁₋₆alkyl-C(R¹²)═N—O—R¹², substituted with —C(═O)—NR¹⁰R¹¹, C₁₋₆alkylsubstituted with —C(═O)—R⁹, C₂₋₆alkynyl substituted with R⁹,hydroxyC₁₋₆alkoxy, C₂₋₆alkenyl, C₂₋₆alkynyl, R¹³ or C₁₋₆alkylsubstituted with C₁₋₆alkoxyC₁₋₆alkyl-C(═O)—.

In one embodiment R³ represents C₁₋₆alkyl, hydroxyC₁₋₆alkyl,haloC₁₋₆alkyl optionally substituted with —O—C(═O)—C₁₋₆alkyl,hydroxyhaloC₁₋₆alkyl, hydroxyC₂₋₆alkynyl, C₁₋₆alkyl substituted with—C(═O)—C₁₋₆alkyl, C₁₋₆alkoxyC₁₋₆alkyl wherein each C₁₋₆alkyl mayoptionally be substituted with one or two hydroxyl groups or with—O—C(═O)—C₁₋₆alkyl, C₁₋₆alkyl substituted with R⁹, cyanoC₁₋₆alkyl,C₁₋₆alkyl substituted with —NR¹⁰R¹¹, C₁₋₆alkyl substituted with hydroxyland —NR¹⁰R¹¹, C₁₋₆alkyl substituted with one or two halo atoms and—NR¹⁰R¹¹. C₁₋₆alkyl substituted with —C(═O)—O—C₁₋₆alkyl, substitutedwith C₁₋₆alkoxyC₁₋₆alkyl-C(═O)—, C₁₋₆alkyl substituted with—C(═O)—NR¹⁰R¹¹, C₁₋₆alkyl substituted with —C(═O)—NR¹⁴R¹⁵, C₁₋₆alkylsubstituted with carboxyl, C₁₋₆alkyl substituted with —O—C(═O)—NR¹⁰R¹¹,C₁₋₆alkyl substituted with —NR¹²—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substitutedwith —NR¹²—S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with R⁹ and substitutedwith —O—C(═O)—C₁₋₆alkyl, C₁₋₆alkyl substituted with hydroxyl and R⁹,—C₁₋₆alkyl-C(R¹²)═N—O—R¹², —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with—S(═O)₂—C₁₋₆alkyl, substituted with —C(═O)—R⁹, C₂₋₆alkenyl substitutedwith R⁹, C₂₋₆alkynyl substituted with R⁹, C₁₋₆alkyloxyC₁₋₆alkyl whereineach C₁₋₆alkyl may optionally be substituted with one or two hydroxylgroups, C₂₋₆alkenyl, C₂₋₆alkynyl, R¹³, or C₁₋₆alkyl substituted with—P(═O)(OC₁₋₆alkyl)₂.

In one embodiment, R³ represents C₁₋₆alkyl, hydroxyC₁₋₆alkyl,hydroxyhaloC₁₋₆alkyl, haloC₁₋₆alkyl, C₁₋₆alkyl substituted with—C(═O)—C₁₋₆alkyl, C₁₋₆alkoxyC₁₋₆alkyl wherein each C₁₋₆alkyl mayoptionally be substituted with one or two hydroxyl groups, C₁₋₆alkylsubstituted with R⁹, C₁₋₆alkyl substituted with —NR¹⁰R¹¹, C₁₋₆alkylsubstituted with hydroxyl and —NR¹⁰R¹¹, C₁₋₆alkyl substituted with oneor two halogens and —NR¹⁰R¹¹, C₁₋₆alkyl substituted with—C(═O)—O—C₁₋₆alkyl, C₁₋₆alkyl substituted with —O—C(═O)—NR¹⁰R¹¹,C₁₋₆alkyl substituted with carboxyl, C₁₋₆alkyl substituted with—NR¹²—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with —NR¹²—S(═O)₂—NR¹⁴R¹⁵,C₁₋₆alkyl substituted with hydroxyl and R⁹, —C₁₋₆alkyl-C(R¹²)═N—O—R¹²,C₁₋₆alkyl substituted with —C(═O)—NR¹⁰R¹¹, substituted with —C(═O)—R⁹,C₂₋₆alkynyl substituted with R⁹, hydroxyC₁₋₆alkoxy, C₂₋₆alkenyl,C₂₋₆alkynyl or R¹³.

In one embodiment, R³ represents C₁₋₆alkyl, hydroxyC₁₋₆alkyl,hydroxyhaloC₁₋₆alkyl, C₁₋₆alkyl substituted with —C(═O)—C₁₋₆alkyl,C₁₋₆alkoxyC₁₋₆alkyl wherein each C₁₋₆alkyl may optionally be substitutedwith one or two hydroxyl groups, C₁₋₆alkyl substituted with R⁹,C₁₋₆alkyl substituted with —NR¹⁰R¹¹, C₁₋₆alkyl substituted with hydroxyland —NR¹⁰R¹¹, C₁₋₆alkyl substituted with one or two halogens and—NR¹⁰R¹¹, C₁₋₆alkyl substituted with —C(═O)—O—C₁₋₆alkyl, C₁₋₆alkylsubstituted with —O—C(═O)—NR¹⁰R¹¹, C₁₋₆alkyl substituted with carboxyl,C₁₋₆alkyl substituted with —NR¹²—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substitutedwith —NR¹²—S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with hydroxyl and R⁹,—C₁₋₆alkyl-C(R¹²)═N—O—R¹², C₁₋₆alkyl substituted with —C(═O)—NR¹⁰R¹¹,substituted with —C(═O)—R⁹, hydroxyC₁₋₆alkoxy, C₂₋₆alkenyl or R¹³.

In one embodiment R³ represents hydroxyC₁₋₆alkyl, haloC₁₋₆alkyl orC₁₋₆alkyl substituted with R⁹.

In one embodiment R³ represents hydroxyC₁₋₆alkyl, C₁₋₆alkyl substitutedwith —NR¹⁰R¹¹ or C₁₋₆alkyl substituted with R⁹.

In one embodiment R³ represents hydroxyC₁₋₆alkyl, haloC₁₋₆alkyl,C₁₋₆alkyl substituted with —NR¹⁰R¹¹, or C₁₋₆alkyl substituted with R⁹.

In one embodiment R³ represents hydroxyC₁₋₆alkyl, haloC₁₋₆alkyl,C₁₋₆alkyl substituted with —NR¹⁰R¹¹, or C₁₋₆alkyl substituted with R⁹;R¹⁰ and R¹¹ each independently represent hydrogen or C₁₋₆alkyl.

In one embodiment R³ represents hydroxyC₁₋₆alkyl, hydroxyhaloC₁₋₆alkyl,haloC₁₋₆alkyl, C₁₋₆alkyl substituted with R⁹, C₁₋₆alkyl substituted with—NR¹⁰R¹¹, C₂₋₆alkynyl substituted with R⁹, or C₂₋₆alkynyl.

In one embodiment R³ represents hydroxyC₁₋₆alkyl, haloC₁₋₆alkyl,C₁₋₆alkyl substituted with R⁹, C₁₋₆alkyl substituted with —NR¹⁰R¹¹,C₁₋₆alkoxyC₁₋₆alkyl, or C₂₋₆alkynyl.

In one embodiment R³ represents hydroxyC₁₋₆alkyl, hydroxyhaloC₁₋₆alkyl,C₁₋₆alkyl substituted with R⁹, C₁₋₆alkyl substituted with —NR¹⁰R¹¹,C₂₋₆alkynyl substituted with R⁹, or C₂₋₆alkynyl.

In one embodiment R³ represents C₁₋₆alkyl (e.g. C₁₋₄alkyl) substitutedwith R⁹.

In one embodiment when R³ represents C₁₋₆alkyl (e.g. C₁₋₄alkyl)substituted with R⁹, R⁹ represents an optionally substituted saturatedor an aromatic 5 or 6 membered monocyclic heterocyclyl, for exampleoptionally substituted isoxazolidinyl, pyrimidinyl, imidazolyl orpyrrolidinyl, in particular optionally substituted imidazolyl (e.g.imidazol-2-yl). In one embodiment, imidazolyl is substituted with—S(═O)₂—NR¹⁴R¹⁵ (e.g. —S(═O)₂—N(CH₃)₂. In one embodiment, R⁹ representsunsubstituted imidazolyl (e.g. imidazol-2-yl).

In one embodiment when R³ represents C₁₋₆alkyl (e.g. C₁₋₄alkyl)substituted with R⁹, R⁹ represents an optionally substituted aromatic 6membered monocyclic heterocyclyl containing one or two nitrogenheteroatom, for example pyrimidinyl or pyridinyl.

In one embodiment when R³ represents C₁₋₆alkyl (e.g. C₁₋₄alkyl)substituted with R⁹, R⁹ represents an optionally substituted 5 memberedaromatic heterocycle, such as for example imidazolyl. Optionalsubstituents may represent S(═O)₂—NR¹⁴R¹⁵.

In one embodiment when R³ represents C₁₋₆alkyl (e.g. C₁₋₄alkyl)substituted with R⁹, R⁹ represents a substituted 5 membered aromaticheterocycle, such as for example imidazolyl.

In one embodiment when R³ represents C₁₋₆alkyl (e.g. C₁₋₄alkyl)substituted with R⁹, R⁹ represents an optionally substituted saturated 5or 6 membered monocyclic heterocyclyl, for example optionallysubstituted isoxazolidinyl or pyrrolidinyl, in particular optionallysubstituted pyrrolidinyl. In one embodiment the pyrrolidinyl issubstituted with oxo. In one embodiment the pyrrolidinyl substitutedwith oxo is pyrrolidin-2-yl substituted with oxo.

In one embodiment when R³ represents C₁₋₈alkyl (e.g. methyl or n-propyl)substituted with R⁹, R⁹ represents C₃₋₈cycloalkyl, for examplecyclopropyl.

In one embodiment R³ represents C₁₋₈alkyl substituted with hydroxyl,halo and/or —NR¹⁰R¹¹. In one embodiment R³ represents C₁₋₈alkylsubstituted with hydroxyl, halo or —NR¹⁰R¹¹, wherein the C₁₋₈alkyl groupis a straight chain alkyl group e.g. 2-ethyl, n-propyl. In a furtherembodiment R³ represents C₁₋₈alkyl substituted with hydroxyl or halo.

In one embodiment R³ represents hydroxyC₁₋₈alkyl. R³ may representCH₂CH₂OH or CH₂CH₂CH₂OH.

In one embodiment R³ represents hydroxyhaloC₁₋₈alkyl, for example R³ mayrepresent CH₂CHOHCF₃.

In one embodiment R³ represents haloC₁₋₈alkyl, for example R³ mayrepresent CH₂CH₂CH₂Cl.

In one embodiment R³ represents C₁₋₈alkyl substituted with —NR¹⁰R¹¹.

In one embodiment R³ represents C₁₋₄alkyl substituted with —NR¹⁰R¹¹. Inone embodiment R³ represents C₁₋₄alkyl substituted —NR¹⁰R¹¹, wherein theC₁₋₄alkyl group is a straight chain alkyl group e.g. 2-ethyl, n-propyl.In one embodiment R³ represents C₁₋₄alkyl substituted with —NR¹⁰R¹¹,wherein the C₁₋₄alkyl group is an ethylene group (—CH₂CH₂—).

In one embodiment when R³ represents C₁₋₈alkyl (e.g. 2-ethyl, n-propyl)substituted with —NR¹⁰R¹¹; R¹⁰ and R¹¹ are independently selected fromhydrogen, C₁₋₈alkyl and haloC₁₋₆alkyl (e.g. hydrogen, iso-propyl or—CH₂CF₃).

In one embodiment, R³ is hydroxyC₁₋₈alkyl, C₁₋₈alkyl substituted withR⁹, or C₁₋₈alkyl substituted with —NR¹⁰R¹¹; in particular R³ isC₁₋₈alkyl substituted with R⁹, or C₁₋₈alkyl substituted with —NR¹⁰R¹¹;more in particular R³ is C₁₋₈alkyl substituted with R⁹.

In one embodiment R^(3a) represents —NR¹⁰R¹¹, hydroxyl, C₁₋₆alkyl,hydroxyC₁₋₆alkyl, hydroxyhaloC₁₋₆alkyl, C₁₋₆alkyl substituted with—C(═O)—C₁₋₆alkyl, C₁₋₆alkoxyC₁₋₆alkyl wherein each C₁₋₆alkyl mayoptionally be substituted with one or two hydroxyl groups, C₁₋₆alkylsubstituted with R⁹, C₁₋₆alkyl substituted with —NR¹⁰R¹¹, C₁₋₆alkylsubstituted with hydroxyl and —NR¹⁰R¹¹, C₁₋₆alkyl substituted with oneor two halogens and —NR¹⁰R¹¹, C₁₋₆alkyl substituted with—C(═O)—O—C₁₋₆alkyl, substituted with —O—C(═O)—NR¹⁰R¹¹, C₁₋₆alkylsubstituted with carboxyl, C₁₋₆alkyl substituted with —O—C(═O)—NR¹⁰R¹¹,C₁₋₆alkyl substituted with —NR¹²—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substitutedwith —NR¹²—S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with hydroxyl and R⁹,—C₁₋₆alkyl-C(R¹²)═N—O—R¹², C₁₋₆alkyl substituted with —C(═O)—NR¹⁰R¹¹,substituted with —C(═O)—R⁹, C₂₋₆alkynyl substituted with R⁹,hydroxyC₁₋₆alkoxy, C₂₋₆alkenyl, C₂₋₆alkynyl, R¹³ or C₁₋₆alkylsubstituted with C₁₋₆alkoxyC₁₋₆alkyl-C(═O)—.

In one embodiment R^(3a) is —NR¹⁰R¹¹, hydroxyl, hydroxyC₁₋₆alkyl,cyanoC₁₋₆alkyl, substituted with —C(═O)—C₁₋₆alkyl, C₁₋₆alkyl substitutedwith —C(═O)—O—C₁₋₆alkyl, substituted with R⁹, C₁₋₆alkyl substituted with—NR¹⁰R¹¹, C₁₋₆alkyl substituted with hydroxyl and —NR¹⁰R¹¹, or C₁₋₆alkylsubstituted with —C(═O)—NR¹⁰R¹¹.

In one embodiment R^(3a) is hydroxyl, C₁₋₆alkyl, hydroxyC₁₋₆alkyl,C₁₋₆alkyl substituted with —C(═O)—O—C₁₋₆alkyl, C₁₋₆alkyl substitutedwith R⁹.

In one embodiment R^(3a) is C₁₋₆alkyl substituted with R⁹.

In one embodiment R^(3a) is C₁₋₆alkyl substituted with—C(═O)—O—C₁₋₆alkyl, for example —CH₂—C(═O)—O—CH₃.

In one embodiment R^(3a) represents hydroxyl.

In one embodiment R^(3b) represents hydrogen.

In one embodiment R^(3b) represents hydroxyl.

In one embodiment R^(3a) represents hydroxyl and R^(3b) representshydrogen.

In one embodiment R^(3a) and R^(3b) are taken together to form ═O, toform ═NR¹⁰, to form cyclopropyl together with the carbon atom to whichthey are attached, to form ═CH—C₀₋₄alkyl substituted with R^(3c), or toform

wherein ring A is a monocyclic 5 to 7 membered saturated heterocyclecontaining one heteroatom selected from N, O or S, said heteroatom notbeing positioned in alpha position of the double bond, wherein ring A isoptionally being substituted with cyano, C₁₋₄alkyl, hydroxyC₁₋₄alkyl,H₂N—C₁₋₄alkyl, (C₁₋₄alkyl)NH—C₁₋₄alkyl, (C₁₋₄alkyl)₂N—C₁₋₄alkyl,(haloC₁₋₄alkyl)NH—C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, —C(═O)—NH₂,—C(═O)—NH(C₁₋₄alkyl), —C(═O)—N(C₁₋₄alkyl)₂.

In one embodiment R^(3a) and R^(3b) are taken together to form ═O, toform cyclopropyl together with the carbon atom to which they areattached, to form ═CH—C₀₋₄alkyl substituted with R^(3c), or to form

wherein ring A is a monocyclic 5 to 7 membered saturated heterocyclecontaining one heteroatom selected from N, O or S, said heteroatom notbeing positioned in alpha position of the double bond.

In one embodiment R^(3a) and R^(3b) are taken together to form ═O.

In one embodiment R^(3a) and R^(3b) are taken together to formcyclopropyl together with the carbon atom to which they are attached.

In one embodiment R^(3a) and R^(3b) are taken together to form═CH—C₀₋₄alkyl substituted with R^(3c), for example ═CH—CH₂—R^(3c) or═CH—R^(3c).

In one embodiment R^(3c) represents hydrogen.

In one embodiment R^(3c) represents hydroxyl, C₁₋₆alkoxy, R⁹, —NR¹⁰R¹¹,—C(═O)—NR¹⁴R¹⁵, cyano, —C(═O)—C₁₋₆alkyl or —CH(OH)—C₁₋₆alkyl.

In one embodiment R^(3c) represents hydroxyl, —C(═O)—NR¹⁴R¹⁵, —NR¹⁰R¹¹,cyano, or —C(═O)—C₁₋₆alkyl.

In one embodiment R^(3a) and R^(3b) are taken together to form═CH—C₀₋₄alkyl (for example ═CH—CH₂— or ═CH—) substituted with R^(3c)wherein R^(3c) represents hydroxyl or —C(═O)—NR¹⁴R¹⁵, for example—C(═O)NH(CH₃).

In one embodiment R^(3a) and R^(3b) are taken together to form═CH—C₁₋₄alkyl in the Z configuration.

In one embodiment R^(3a) and R^(3b) are taken together to form═CH—C₁₋₄alkyl in the E configuration.

In one embodiment R^(3a) represents —NR¹⁰R¹¹, hydroxyl, C₁₋₆alkoxy,hydroxyC₁₋₆alkoxy, C₁₋₆alkoxy substituted with —NR¹⁰R¹¹, C₁₋₆alkyl,C₂₋₆alkynyl, haloC₁₋₆alkyl optionally substituted with—O—C(═O)—C₁₋₆alkyl, hydroxyC₁₋₆alkyl optionally substituted with—O—C(═O)—C₁₋₆alkyl, hydroxyC₂₋₆alkynyl, hydroxyhaloC₁₋₆alkyl,cyanoC₁₋₆alkyl, C₁₋₆alkyl substituted with carboxyl, C₁₋₆alkylsubstituted with —C(═O)—C₁₋₆alkyl, C₁₋₆alkyl substituted with—C(═O)—O—C₁₋₆alkyl, C₁₋₆alkyl substituted withC₁₋₆alkoxyC₁₋₆alkyl-O—C(═O)—, C₁₋₆alkyl substituted withC₁₋₆alkoxyC₁₋₆alkyl-C(═O)—, C₁₋₆alkyl substituted with—O—C(═O)—C₁₋₆alkyl, C₁₋₆alkoxyC₁₋₆alkyl wherein each C₁₋₆alkyl mayoptionally be substituted with one or two hydroxyl groups or with—O—C(═O)—C₁₋₆alkyl, C₂₋₆alkynyl substituted with C₁₋₆alkoxy, C₁₋₆alkylsubstituted with R⁹ and optionally substituted with —O—C(═O)—C₁₋₆alkyl,C₁₋₆alkyl substituted with —C(═O)—R⁹, C₁₋₆alkyl substituted withhydroxyl and R⁹, C₂₋₆alkynyl substituted with R⁹, C₁₋₆alkyl substitutedwith —NR¹⁰R¹¹, C₂₋₆alkynyl substituted with —NR¹⁰R¹¹, C₁₋₆alkylsubstituted with hydroxyl and —NR¹⁰R¹¹, C₁₋₆alkyl substituted with oneor two halogens and —NR¹ r<_C₁₋₆alkyl-C(R¹²)═N—O—R¹², C₁₋₆alkylsubstituted with —C(═O)—NR¹⁰R¹¹, C₁₋₆alkyl substituted with—O—C(═O)—NR¹⁰R¹¹, —S(═O)₂—C₁₋₆alkyl, —S(═O)₂-haloC₁₋₆alkyl,—S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with —S(═O)₂—C₁₋₆alkyl, C₁₋₆alkylsubstituted with —S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with—S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with —NR¹²—S(═O)₂—C₁₋₆alkyl,substituted with —NH—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with—NR¹²—S(═O)₂—NR¹⁴R¹⁵, R¹³, C₁₋₆alkyl substituted with —P(═O)(OH)₂ orC₁₋₆alkyl substituted with —P(═O)(OC₁₋₆alkyl)₂;

R^(3b) represents hydrogen or hydroxyl; provided that if R^(3a)represents —NR¹⁰R¹¹, then R^(3b) represents hydrogen; or

R^(3a) and R^(3b) are taken together to form ═O, to form ═NR¹⁰, to formcyclopropyl together with the carbon atom to which they are attached, toform ═CH—C₀₋₄alkyl substituted with R^(3c), or to form

wherein ring A is a monocyclic 5 to 7 membered saturated heterocyclecontaining one heteroatom selected from N, O or S, said heteroatom notbeing positioned in alpha position of the double bond, wherein ring A isoptionally being substituted with cyano, C₁₋₄alkyl, hydroxyC₁₋₄alkyl,(C₁₋₄alkyl)₂N—C₁₋₄alkyl, (haloC₁₋₄alkyl)NH—C₁₋₄alkyl,C₁₋₄alkoxyC₁₋₄alkyl, —C(═O)—NH₂, —C(═O)—NH(C₁₋₄alkyl),—C(═O)—N(C₁₋₄alkyl)₂.

In one embodiment R^(3a) represents —NR¹⁰R¹¹, hydroxyl, C₁₋₆alkoxy,hydroxyC₁₋₆alkoxy, C₁₋₆alkoxy substituted with —NR¹⁰R¹¹, C₁₋₆alkyl,C₂₋₆alkenyl, haloC₁₋₆alkyl optionally substituted with—O—C(═O)—C₁₋₆alkyl, hydroxyC₁₋₆alkyl optionally substituted with—O—C(═O)—C₁₋₆alkyl, hydroxyC₂₋₆alkenyl, hydroxyhaloC₁₋₆alkyl,cyanoC₁₋₆alkyl, substituted with carboxyl, C₁₋₆alkyl substituted with—C(═O)—C₁₋₆alkyl, C₁₋₆alkyl substituted with —C(═O)—O—C₁₋₆alkyl,C₁₋₆alkyl substituted with C₁₋₆alkoxyC₁₋₆alkyl-O—C(═O)—, C₁₋₆alkylsubstituted with C₁₋₆alkoxyC₁₋₆alkyl-C(═O)—, C₁₋₆alkyl substituted with—O—C(═O)—C₁₋₆alkyl, C₁₋₆alkoxyC₁₋₆alkyl wherein each C₁₋₆alkyl mayoptionally be substituted with one or two hydroxyl groups or with—O—C(═O)—C₁₋₆alkyl, C₂₋₆alkenyl substituted with C₁₋₆alkoxy, C₁₋₆alkylsubstituted with R⁹ and optionally substituted with —O—C(═O)—C₁₋₆alkyl,C₁₋₆alkyl substituted with —C(═O)—R⁹, C₁₋₆alkyl substituted withhydroxyl and R⁹, C₂₋₆alkenyl substituted with R⁹, C₁₋₆alkyl substitutedwith —NR¹⁰R¹¹, C₂₋₆alkenyl substituted with —NR¹⁰R¹¹, C₁₋₆alkylsubstituted with hydroxyl and —NR¹⁰R¹¹, C₁₋₆alkyl substituted with oneor two halogens and —NR¹⁰R¹¹, —C₁₋₆alkyl-C(R¹²)═N—O—R¹², C₁₋₆alkylsubstituted with C₁₋₆alkyl substituted with —O—C(═O)—NR¹⁰R¹¹,—S(═O)₂—C₁₋₆alkyl, —S(═O)₂-haloC₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkylsubstituted with —S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with —S(═O)₂—NR¹⁴R¹⁵,C₁₋₆alkyl substituted with —NR¹²—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substitutedwith —NH—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with—NR¹²—S(═O)₂—NR¹⁴R¹⁵, R¹³, C₁₋₆alkyl substituted with —P(═O)(OH)₂ orC₁₋₆alkyl substituted with —P(═O)(OC₁₋₆alkyl)₂;

R^(3b) represents hydrogen or hydroxyl; provided that if R^(3a)represents —NR¹⁰R¹¹, then R^(3b) represents hydrogen; or

R^(3a) and R^(3b) are taken together to form ═O, to form ═NR¹⁰, to formcyclopropyl together with the carbon atom to which they are attached, toform ═CH—C₀₋₄alkyl substituted with R^(3c), or to form

wherein ring A is a monocyclic 5 to 7 membered saturated heterocyclecontaining one heteroatom selected from N, O or S, said heteroatom notbeing positioned in alpha position of the double bond, wherein ring A isoptionally being substituted with cyano, C₁₋₄alkyl, hydroxyC₁₋₄alkyl,(C₁₋₄alkyl)₂N—C₁₋₄alkyl, (haloC₁₋₄alkyl)NH—C₁₋₄alkyl,C₁₋₄alkoxyC₁₋₄alkyl, —C(═O)—NH₂, —C(═O)—NH(C₁₋₄alkyl),—C(═O)—N(C₁₋₄alkyl)₂.

In one embodiment R^(3a) represents —NR¹⁰R¹¹, hydroxyl, C₁₋₆alkoxy,hydroxyC₁₋₆alkoxy, C₁₋₆alkoxy substituted with —NR¹⁰R¹¹, C₁₋₆alkyl,haloC₁₋₆alkyl optionally substituted with —O—C(═O)—C₁₋₆alkyl,hydroxyC₁₋₆alkyl optionally substituted with —O—C(═O)—C₁₋₆alkyl,hydroxyhaloC₁₋₆alkyl, cyanoC₁₋₆alkyl, C₁₋₆alkyl substituted withcarboxyl, C₁₋₆alkyl substituted with —C(═O)—C₁₋₆alkyl, C₁₋₆alkylsubstituted with —C(═O)—O—C₁₋₆alkyl, substituted withC₁₋₆alkoxyC₁₋₆alkyl-O—C(═O)—, C₁₋₆alkyl substituted withC₁₋₆alkoxyC₁₋₆alkyl-C(═O)—, C₁₋₆alkyl substituted with—O—C(═O)—C₁₋₆alkyl, C₁₋₆alkoxyC₁₋₆alkyl wherein each C₁₋₆alkyl mayoptionally be substituted with one or two hydroxyl groups or with—O—C(═O)—C₁₋₆alkyl, C₁₋₆alkyl substituted with R⁹ and optionallysubstituted with —O—C(═O)—C₁₋₆alkyl, C₁₋₆alkyl substituted with—C(═O)—R⁹, C₁₋₆alkyl substituted with hydroxyl and R⁹, C₁₋₆alkylsubstituted with —NR¹⁰R¹¹, C₁₋₆alkyl substituted with hydroxyl and—NR¹⁰R¹¹, C₁₋₆alkyl substituted with one or two halogens and —NR¹⁰R¹¹,—C₁₋₆alkyl-C(R¹²)═N—O—R¹², C₁₋₆alkyl substituted with —C(═O)—NR¹⁰R¹¹,—C₁₋₆alkyl substituted with —O—C(═O)—NR¹⁰R¹¹, —S(═O)₂—C₁₋₆alkyl,—S(═O)₂-haloC₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with —S(═O)₂-haloC₁₋₆alkyl,C₁₋₆alkyl substituted with —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with—NR¹²—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with—NH—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with—NR¹²—S(═O)₂—NR¹⁴R¹⁵, R¹³, C₁₋₆alkyl substituted with —P(═O)(OH)₂ orC₁₋₆alkyl substituted with —P(═O)(OC₁₋₆alkyl)₂;

R^(3b) represents hydrogen or hydroxyl; provided that if R^(3a)represents —NR¹⁰R¹¹, then R^(3b) represents hydrogen; or

R^(3a) and R^(3b) are taken together to form ═O, to form ═NR¹⁰, to formcyclopropyl together with the carbon atom to which they are attached, toform ═CH—C₀₋₄alkyl substituted with R^(3c), or to form

wherein ring A is a monocyclic 5 to 7 membered saturated heterocyclecontaining one heteroatom selected from N, O or S, said heteroatom notbeing positioned in alpha position of the double bond, wherein ring A isoptionally being substituted with cyano, C₁₋₄alkyl, hydroxyC₁₋₄alkyl,H₂N—C₁₋₄alkyl, (C₁₋₄alkyl)NH—C₁₋₄alkyl, (C₁₋₄alkyl)₂N—C₁₋₄alkyl,(haloC₁₋₄alkyl)NH—C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, —C(═O)—NH₂,—C(═O)—NH(C₁₋₄alkyl), —C(═O)—N(C₁₋₄alkyl)₂.

In one embodiment, R^(3a) is not alkenyl or substituted alkenyl.

In one embodiment, R^(3a) is not alkynyl or substituted alkynyl.

In one embodiment, R^(3a) is not alkenyl, substituted alkenyl, alkynylor substituted alkynyl.

In one embodiment, R⁹ is selected from:

an optionally substituted C₃₋₈cycloalkyl,

an optionally substituted aromatic 5 membered monocyclic heterocyclyl,

an optionally substituted saturated 6 membered monocyclic heterocyclyl,

a saturated or an aromatic 3, 4, 5 or 6 membered monocyclic heterocyclylcontaining one or two oxygen heteroatoms,

an optionally substituted 4 membered heterocyclyl containing one oxygenheteroatom,

an optionally substituted aromatic 6 membered monocyclic heterocyclecontaining one or two nitrogen heteroatoms,

a partially saturated 6 membered monocyclic heterocyclyl containing onenitrogen heteroatom which may optionally be substituted,

an optionally substituted saturated 4 membered monocyclic heterocyclylcontaining one nitrogen heteroatom,

a saturated 5 membered monocyclic heterocyclyl containing one nitrogenheteroatom,

a saturated 6 membered monocyclic heterocyclyl containing one nitrogenheteroatom,

a bicyclic heterocyclyl containing a benzene ring fused to a 5- or6-membered ring containing 1, 2 or 3 ring heteroatoms,

a 4, 5 or 6 membered monocyclic saturated heterocycle substituted withtwo substituents which are attached to the same atom and which are takentogether to form a 4 to 7-membered saturated monocyclic heterocyclylcontaining at least one heteroatom selected from N, O or S,

an optionally substituted aromatic 5 membered monocyclic heterocyclylcontaining one sulphur heteroatom,

an optionally substituted aromatic 5 membered monocyclic heterocyclylcontaining one sulphur and one nitrogen heteroatom,

a saturated 6 membered monocyclic heterocyclyl containing two nitrogenheteroatoms,

an aromatic 5 membered monocyclic heterocyclyl containing four nitrogenheteroatoms,

an aromatic 5 membered monocyclic heterocyclyl containing one oxygen andtwo nitrogen heteroatoms,

an optionally substituted aromatic 5 membered monocyclic heterocyclylcontaining two nitrogen heteroatoms,

an optionally substituted aromatic 5 membered monocyclic heterocyclylcontaining three nitrogen heteroatoms,

a saturated 5 membered monocyclic heterocyclyl containing one nitrogenand one oxygen heteroatom,

a saturated 6 membered monocyclic heterocyclyl containing one nitrogenand one sulphur heteroatom,

a saturated 7 membered monocyclic heterocyclyl containing two nitrogenheteroatoms,

a saturated 7 membered monocyclic heterocyclyl containing one nitrogenand one oxygen heteroatom, and

phenyl or naphthyl, in particular phenyl.

In one embodiment, R⁹ represents an optionally substituted 5 memberedaromatic or saturated heterocycle, such as for example imidazolyl,pyrolidinyl, isoxazolidinyl. Optional substituents may represent ═O, a 5or 6-membered aromatic monocyclic heterocyclyl containing at least oneheteroatom selected from N, O or S wherein said heterocyclyl isoptionally substituted with R¹⁶; or S(═O)₂—NR¹⁴R¹⁶.

In one embodiment, R⁹ represents C₃₋₆cycloalkyl, such as for examplecyclopropyl, a 3 membered saturated heterocyclyl, such as for exampleoxiranyl, an optionally substituted 5 membered saturated heterocycle,such as for example pyrolidinonyl, an optionally substituted 6 memberedaromatic or saturated heterocycle, such as for example pyridyl,pyrimidinyl, pyrazinyl, piperazinyl, or morpholinyl, an optionallysubstituted bicyclic heterocycle, such as for example1H-isoindol-1,3-dione. Optional substituents may represent ═O,C₁₋₄alkoxy, C₁₋₄alkyl substituted with NR¹⁴R¹⁶, hydroxyC₁₋₄alkyl, orC₁₋₄alkyl-C(═O)—.

In one embodiment, R⁹ represents an optionally substituted 5 memberedaromatic heterocycle, such as for example imidazolyl, or an optionallysubstituted 6 membered aromatic heterocycle, such as for examplepyridyl, pyrimidinyl or pyrazinyl. Optional substituents may representC₁₋₄alkoxy or S(═O)₂—NR¹⁴R¹⁶.

In one embodiment, R⁹ represents an optionally substituted 5 memberedaromatic heterocycle, such as for example imidazolyl. Optionalsubstituents may represent S(═O)₂—NR¹⁴R¹⁵.

In one embodiment, R⁹ represents an optionally substituted 6 memberedaromatic heterocycle, such as for example pyridinyl or pyrimidinyl.Optional substituents may represent C₁₋₄alkoxy.

In one embodiment, R⁹ represents an optionally substituted 5 memberedaromatic or saturated heterocycle, such as for example imidazolyl,pyrolidinyl, oxazolidinyl. Optional substituents may represent ═O, a 5or 6-membered aromatic monocyclic heterocyclyl containing at least oneheteroatom selected from N, O or S wherein said heterocyclyl isoptionally substituted with R¹⁶; or S(═O)₂—NR¹⁴R¹⁵.

In one embodiment, R⁹ represents C₃₋₆cycloalkyl, such as for examplecyclopropyl, a 3 membered saturated heterocyclyl, such as for exampleoxiranyl, an optionally substituted 5 membered saturated heterocycle,such as for example pyrolidinonyl, an optionally substituted 6 memberedaromatic or saturated heterocycle, such as for example pyridyl,pyrimidinyl, pyrazinyl, piperazinyl, or morpholinyl, an optionallysubstituted bicyclic heterocycle, such as for example1H-isoindol-1,3-dione. Optional substituents may represent ═O,C₁₋₄alkoxy, C₁₋₄alkyl substituted with NR¹⁴R¹⁵, hydroxyC₁₋₄alkyl, orC₁₋₄alkyl-C(═O)—.

In one embodiment, R⁹ is imidazolyl, in particular 2-imidazolyl,optionally substituted with —S(═O)₂—NR¹⁴R¹⁵; in particular R⁹ isimidazolyl, in particular 2-imidazolyl.

In one embodiment R¹⁰ represents hydrogen or C₁₋₆alkyl.

In one embodiment R¹⁰ is hydrogen.

In one embodiment R¹¹ represents hydrogen, C₁₋₆alkyl, haloC₁₋₆alkyl,—C(═O)—C₁₋₆alkyl, —S(═O)₂—C₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵, hydroxyC₁₋₆alkyl,—C(═O)-hydroxyhaloC₁₋₆alkyl, —C(═O)—R⁶, cyanoC₁₋₆alkyl, R⁶, —C(═O)—R⁶,C₁₋₆alkyl substituted with R⁶, —C(═O)-haloC₁₋₆alkyl, C₁₋₆alkylsubstituted with Si(CH₃)₃, C₁₋₆alkyl substituted with NR¹⁴R¹⁵, C₁₋₆alkylsubstituted with —C(═O)—NR¹⁴R¹⁵, C₁₋₆alkoxy, hydroxyhaloC₁₋₆alkyl,carboxyl, or C₁₋₆alkoxyC₁₋₆alkyl.

In one embodiment R¹⁰ and R¹¹ represent hydrogen or C₁₋₆alkyl.

In one embodiment, R⁶ represents a 6-membered monocyclic saturatedheterocyclyl which is optionally substituted. For example piperazinyl ormorpholinyl or tetrahydropyranyl, optionally substituted with halogen,C₁₋₆alkyl, or C₁₋₆alkyl-O—C(═O)—.

In one embodiment, R⁶ represents a 6-membered monocyclic aromaticheterocyclyl which is optionally substituted. For example pyridinyl,optionally substituted with halogen, C₁₋₆alkyl, or C₁₋₆alkyl-O—C(═O)—.

In one embodiment R⁶ represents an optionally substituted saturated 4 to7-membered monocyclic heterocyclyl containing at least one heteroatomselected from N, O or S, such as for example tetrahydropyran.

In one embodiment, R⁶ represents C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, 4 to7-membered monocyclic heterocyclyl containing at least one heteroatomselected from N, O or S; said C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, 4 to7-membered monocyclic heterocyclyl, optionally and each independentlybeing substituted by 1, 2, 3, 4 or 5 substituents, each substituentindependently being selected from cyano, C₁₋₆alkyl, cyanoC₁₋₆alkyl,hydroxyl, carboxyl, hydroxyC₁₋₆alkyl, halogen, haloC₁₋₆alkyl,hydroxyhaloC₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkoxyC₁₋₆alkyl, —NR¹⁴R¹⁵,—C(═O)—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with —NR¹⁴R¹⁵, C₁₋₆alkylsubstituted with —C(═O)—NR¹⁴R¹⁵, —S(═O)₂—C₁₋₆alkyl,—S(═O)₂-haloC₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with —S(═O)₂-haloC₁₋₆alkyl,C₁₋₆alkyl substituted with —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted withNH—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with NH—S(═O)₂-haloC₁₋₆alkylor C₁₋₆alkyl substituted with NH—S(═O)₂—NR¹⁴R¹⁵.

In one embodiment, R¹² represents hydrogen or C₁₋₄alkyl optionallysubstituted with C₁₋₄alkyloxy.

In one embodiment, R¹³ represents a saturated 4 to 6-membered monocyclicheterocyclyl containing at least one heteroatom selected from N or 0.

In one embodiment, R¹⁴ and R¹⁵ each independently represent hydrogen orC₁₋₄alkyl.

In one embodiment, W is —N(R³)—.

In one embodiment, W is —C(R^(3a)R^(3b))—.

In one embodiment, W is —C(═O)—.

In one embodiment, W is —N(R³)— or —C(R^(3a)R^(3b))— wherein R^(3a) andR^(3b) are not taken together to form ═O.

In one embodiment, W is —N(R³)— or —C(R^(3a)R^(3b))— wherein R^(3a)represents —NR¹⁰R¹¹, hydroxyl, C₁₋₆alkoxy, hydroxyC₁₋₆alkoxy, C₁₋₆alkoxysubstituted with —NR¹⁰R¹¹, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,haloC₁₋₆alkyl optionally substituted with —O—C(═O)—C₁₋₆alkyl,hydroxyC₁₋₆alkyl optionally substituted with —O—C(═O)—C₁₋₆alkyl,hydroxyC₂₋₆alkenyl, hydroxyC₂₋₆alkynyl, hydroxyhaloC₁₋₆alkyl,cyanoC₁₋₆alkyl, C₁₋₆alkyl substituted with carboxyl, C₁₋₆alkylsubstituted with —C(═O)—C₁₋₆alkyl, C₁₋₆alkyl substituted with—C(═O)—O—C₁₋₆alkyl, C₁₋₆alkyl substituted withC₁₋₆alkoxyC₁₋₆alkyl-O—C(═O)—, C₁₋₆alkyl substituted withC₁₋₆alkoxyC₁₋₆alkyl-C(═O)—, C₁₋₆alkyl substituted with—O—C(═O)—C₁₋₆alkyl, C₁₋₆alkoxyC₁₋₆alkyl wherein each C₁₋₆alkyl mayoptionally be substituted with one or two hydroxyl groups or with—O—C(═O)—C₁₋₆alkyl, C₂₋₆alkenyl substituted with C₁₋₆alkoxy, C₂₋₆alkynylsubstituted with C₁₋₆alkoxy, C₁₋₆alkyl substituted with R⁹ andoptionally substituted with —O—C(═O)—C₁₋₆alkyl, C₁₋₆alkyl substitutedwith —C(═O)—R⁹, C₁₋₆alkyl substituted with hydroxyl and R⁹, C₂₋₆alkenylsubstituted with R⁹, C₂₋₆alkynyl substituted with R⁹, C₁₋₆alkylsubstituted with —NR¹⁰R¹¹, C₂₋₆alkenyl substituted with —NR¹⁰R¹¹,C₂₋₆alkynyl substituted with —NR¹⁰R¹¹, C₁₋₆alkyl substituted withhydroxyl and —NR¹⁰R¹¹, C₁₋₆alkyl substituted with one or two halogensand —NR¹⁰R¹¹, —C₁₋₆alkyl-C(R¹²)═N—O—R¹², C₁₋₆alkyl substituted with—C(═O)—NR¹⁰R¹¹, C₁₋₆alkyl substituted with —O—C(═O)—NR¹⁰R¹¹,—S(═O)₂—C₁₋₆alkyl, —S(═O)₂-haloC₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkylsubstituted with —S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with —S(═O)₂—NR¹⁴R¹⁵,C₁₋₆alkyl substituted with —NR¹²—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substitutedwith —NH—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with—NR¹²—S(═O)₂—NR¹⁴R¹⁵, R¹³, C₁₋₆alkyl substituted with —P(═O)(OH)₂ orC₁₋₆alkyl substituted with —P(═O)(OC₁₋₆alkyl)₂;

R^(3b) represents hydrogen or hydroxyl; provided that if R^(3a)represents —NR¹⁰R¹¹, then R^(3b) represents hydrogen; or

R^(3a) and R^(3b) are taken together to form ═NR¹⁰, to form cyclopropyltogether with the carbon atom to which they are attached, to form═CH—C₀₋₄alkyl substituted with R^(3c), or to form

wherein ring A is a monocyclic 5 to 7 membered saturated heterocyclecontaining one heteroatom selected from N, O or S, said heteroatom notbeing positioned in alpha position of the double bond, wherein ring A isoptionally being substituted with cyano, hydroxyC₁₋₄alkyl,(C₁₋₄alkyl)₂N—C₁₋₄alkyl, (haloC₁₋₄alkyl)NH—C₁₋₄alkyl,C₁₋₄alkoxyC₁₋₄alkyl, —C(═O)—NH₂, —C(═O)—NH(C₁₋₄alkyl),—C(═O)—N(C₁₋₄alkyl)₂.

In one embodiment, W is —N(R³)— or —C(R^(3a)R^(3b))— wherein R^(3a) andR^(3b) are not taken together.

In one embodiment, W is —N(R³)— or —C(═O)—; in particular W is —N(R³)—;R³ represents hydroxyC₁₋₆alkyl optionally substituted with—O—C(═O)—C₁₋₆alkyl, substituted with R⁹ and optionally substituted with—O—C(═O)—C₁₋₆alkyl, substituted with —NR¹⁰R¹¹.

In one embodiment, W is —N(R³)—, D is a 5 or 6 membered monocyclicaromatic carbocyclyl or heterocyclyl, wherein said carbocyclyl orheterocyclyl may optionally be substituted by one or more (e.g. 1, 2 or3) R¹ groups; n is 2 or 4; R² is C₁₋₆alkyloxy or halo; R³ ishydroxyC₁₋₆alkyl, haloC₁₋₆alkyl or C₁₋₆alkyl substituted with R⁹. In oneembodiment, W is —N(R³)—, D is phenyl, or pyrazolyl substituted withC₁₋₆alkyl; n is 2 or 4; R² is C₁₋₆alkyloxy or halo; R³ ishydroxyC₁₋₆alkyl, haloC₁₋₆alkyl or C₁₋₆alkyl substituted with R⁹.

In one embodiment, W is —N(R³)—, D is a 5 or 6 membered monocyclicaromatic carbocyclyl or heterocyclyl, wherein said carbocyclyl orheterocyclyl may optionally be substituted by one or more (e.g. 1, 2 or3) R¹ groups; n is 2, 3 or 4; R² is C₁₋₆alkyloxy or halo; R³ ishydroxyC₁₋₆alkyl, C₁₋₆alkyl substituted with —NR¹⁰R¹¹, or C₁₋₆alkylsubstituted with R⁹; R¹⁰ and R¹¹ each independently represent hydrogenor C₁₋₆alkyl.

In one embodiment, W is —N(R³)—, D is phenyl, or pyrazolyl substitutedwith C₁₋₆alkyl; n is 2, 3 or 4; R² is C₁₋₆alkyloxy or halo; R³ ishydroxyC₁₋₆alkyl, haloC₁₋₆alkyl, C₁₋₆alkyl substituted with —NR¹⁰R¹¹, orC₁₋₆alkyl substituted with R⁹; R¹⁰ and R¹¹ each independently representhydrogen or C₁₋₆alkyl.

In one embodiment, W is —N(R³)—, D is a 5 or 6 membered monocyclicaromatic carbocyclyl or heterocyclyl, wherein said carbocyclyl orheterocyclyl may optionally be substituted by one or more (e.g. 1, 2 or3) R¹ groups, in particular D is phenyl, or pyrazolyl optionallysubstituted with C₁₋₆alkyl, more in particular D is phenyl, or pyrazolyloptionally substituted with C₁₋₆alkyl, and n is 2 or 4; even more inparticular D is phenyl, or pyrazolyl optionally substituted withC₁₋₆alkyl; n is 2 or 4, R² is C₁₋₆alkyloxy or halo; even further inparticular D is phenyl, or pyrazolyl optionally substituted withC₁₋₆alkyl; n is 2 or 4; R² is C₁₋₆alkyloxy or halo, and said R² isplaced in position 2, 3, 5 or 6; even further in particular D is phenyl,or pyrazolyl optionally substituted with C₁₋₆alkyl; n is 2; R² isC₁₋₆alkyloxy and said R² is placed in position 3 or 5; and R³ ishydroxyC₁₋₆alkyl, haloC₁₋₆alkyl or C₁₋₆alkyl substituted with R⁹.

In one embodiment, W is —C(R^(3a)R^(3b))—, D is a 5 or 6 memberedmonocyclic aromatic carbocyclyl or heterocyclyl, wherein saidcarbocyclyl or heterocyclyl may optionally be substituted by one or more(e.g. 1, 2 or 3) R¹ groups; n is 2 or 4; R² is C₁₋₆alkyloxy or halo; R³is hydroxyC₁₋₆alkyl, haloC₁₋₆alkyl or C₁₋₆alkyl substituted with R⁹. Inone embodiment, W is —C(R^(3a)R^(3b))—, D is phenyl, or pyrazolylsubstituted with C₁₋₆alkyl; n is 2 or 4; R² is C₁₋₆alkyloxy or halo; R³is hydroxyC₁₋₆alkyl, haloC₁₋₆alkyl or C₁₋₆alkyl substituted with R⁹.

In one embodiment, W is —C(R^(3a)R^(3b))—, D is a 5 or 6 memberedmonocyclic aromatic carbocyclyl or heterocyclyl, wherein saidcarbocyclyl or heterocyclyl may optionally be substituted by one or more(e.g. 1, 2 or 3) R¹ groups; in particular D is phenyl, or pyrazolyloptionally substituted with C₁₋₆alkyl, more in particular D is phenyl,or pyrazolyl optionally substituted with C₁₋₆alkyl and n is 2 or 4; evenmore in particular D is phenyl, or pyrazolyl optionally substituted withC₁₋₆alkyl; n is 2 or 4; R² is C₁₋₆alkyloxy or halo; even further inparticular D is phenyl, or pyrazolyl optionally substituted withC₁₋₆alkyl; n is 2 or 4; R² is C₁₋₆alkyloxy and said R² is placed inposition 2, 3, 5 or 6; even further in particular D is phenyl, orpyrazolyl optionally substituted with C₁₋₆alkyl; n is 2 or 4; R² isC₁₋₆alkyloxy and said R² is placed in position 2, 3, 5 or 6; and R³ ishydroxyC₁₋₆alkyl, haloC₁₋₆alkyl or C₁₋₆alkyl substituted with R⁹.

In one embodiment, n represents an integer equal to 2 or 4; R²represents C₁₋₄alkoxy or halogen, for example CH₃O— or fluoro; R³represents hydroxyC₁₋₆alkyl, haloC₁₋₆alkyl or C₁₋₆alkyl substituted withR⁹, D represents pyrazolyl, in particular pyrazol-4-yl substituted withC₁₋₆alkyl; W is —N(R³)—.

In one embodiment,

D is pyrazolyl or phenyl, each optionally substituted with C₁₋₄alkyl;

W is —N(R³)— or —C(═O)—;

R³ is hydroxyC₁₋₆alkyl, C₁₋₆alkyl substituted with R⁹, or

-   -   C₁₋₆alkyl substituted with —NR¹⁰R¹¹;

R⁹ is imidazolyl optionally substituted with —S(═O)₂—NR¹⁴R¹⁵;

R¹⁰ and R¹¹ each independently represent hydrogen or C₁₋₆alkyl;

R¹⁴ and R¹⁵ represent C₁₋₄alkyl.

In one embodiment,

D is pyrazolyl or phenyl, each optionally substituted with C₁₋₄alkyl;

W is —N(R³)—;

R³ is hydroxyC₁₋₆alkyl, C₁₋₆alkyl substituted with R⁹, or

-   -   C₁₋₆alkyl substituted with —NR¹⁰R¹¹;

R⁹ is imidazolyl optionally substituted with —S(═O)₂—NR¹⁴R¹⁵;

R¹⁰ and R¹¹ each independently represent hydrogen or C₁₋₆alkyl;

R¹⁴ and R¹⁵ represent C₁₋₄alkyl.

In one embodiment,

W is —N(R³)— or —C(═O)—; in particular W is —N(R³)—;

each R² is halogen or C₁₋₄alkoxy;

D represents a 5 to 6 ring membered monocyclic carbocyclyl or a 5 to 6ring membered monocyclic heterocyclyl containing at least one heteroatomselected from N, O or S, wherein said carbocyclyl and heterocyclyl mayeach be optionally substituted by one or more (e.g. 1, 2 or 3) R¹groups;

R¹ represents C₁₋₆alkyl;

R³ represents hydroxyC₁₋₆alkyl, C₁₋₆alkyl substituted with R⁹, or

-   -   C₁₋₆alkyl substituted with —NR¹⁰R¹¹;

R⁹ represents a 5 membered monocyclic heterocyclyl containing at leastone heteroatom selected from N, O or S, said 5 membered monocyclicheterocyclyl optionally substituted with —S(═O)₂—NR¹⁴R¹⁵;

R¹⁰ and R¹¹ each independently represent hydrogen or C₁₋₆alkyl;

R¹⁴ and R¹⁵ represent C₁₋₄alkyl;

n independently represents an integer equal to 1, 2, 3 or 4.

In one embodiment,

W is —N(R³)— or —C(═O)—; in particular W is —N(R³)—;

each R² is halogen or C₁₋₄alkoxy;

D represents a 5 to 6 ring membered monocyclic carbocyclyl or a 5 to 6ring membered monocyclic heterocyclyl containing at least one N-atom,wherein said carbocyclyl and heterocyclyl may each be optionallysubstituted by one R¹ group;

R¹ represents C₁₋₆alkyl;

R³ represents hydroxyC₁₋₆alkyl, C₁₋₆alkyl substituted with R⁹, or

-   -   C₁₋₆alkyl substituted with —NR¹⁰R¹¹;

R⁹ represents a 5 membered monocyclic heterocyclyl containing at leastone N-atom, said 5 membered monocyclic heterocyclyl optionallysubstituted with —S(═O)₂—NR¹⁴R¹⁵;

R¹⁰ and R¹¹ each independently represent hydrogen or C₁₋₆alkyl;

R¹⁴ and R¹⁵ represent C₁₋₄alkyl;

n independently represents an integer equal to 1, 2, 3 or 4.

In one embodiment,

W is —N(R³)— or —C(═O)—; in particular W is —N(R³)—;

each R² is fluoro, chloro or methoxy;

D represents phenyl or pyrazolyl substituted with methyl on theNH-group;

R¹ represents methyl;

R³ represents hydroxyethyl, methyl substituted with R⁹, or

-   -   ethyl substituted with —NR¹⁰R¹¹;

R⁹ represents imidazolyl optionally substituted with —S(═O)₂—NR¹⁴R¹⁵;

R¹⁰ and R¹¹ each independently represent hydrogen, ethyl or isopropyl;

R¹⁴ and R¹⁵ represent methyl;

n independently represents an integer equal to 1, 2, 3 or 4.

In one embodiment,

W is —N(R³)— or —C(═O)—; in particular W is —N(R³)—;

each R² is halogen or C₁₋₄alkoxy;

D represents a 3 to 12 ring membered monocyclic or bicyclic carbocyclylor a 3 to 12 ring membered monocyclic or bicyclic heterocyclylcontaining at least one heteroatom selected from N, O or S, wherein saidcarbocyclyl and heterocyclyl may each be optionally substituted by oneor more (e.g. 1, 2 or 3) R¹ groups;

R¹ represents C₁₋₆alkyl;

R³ represents hydroxyC₁₋₆alkyl optionally substituted with—O—C(═O)—C₁₋₆alkyl, C₁₋₆alkyl substituted with R⁹ and optionallysubstituted with —O—C(═O)—C₁₋₆alkyl, C₁₋₆alkyl substituted with—NR¹⁰R¹¹;

R⁹ represents a 3 to 12 membered monocyclic or bicyclic heterocyclylcontaining at least one heteroatom selected from N, O or S, said 3 to 12membered monocyclic or bicyclic heterocyclyl optionally substituted with—S(═O)₂—NR¹⁴R¹⁵;

R¹⁰ and R¹¹ each independently represent hydrogen or C₁₋₆alkyl;

R¹⁴ and R¹⁵ each represent C₁₋₄alkyl;

n independently represents an integer equal to 1, 2, 3 or 4.

In one embodiment,

W is —N(R³)— or —C(R^(3a)R^(3b))—; in particular W is —N(R³)—;

each R² is halogen or C₁₋₄alkoxy;

D represents a 5 to 6 ring membered monocyclic carbocyclyl or a 5 to 6ring membered monocyclic heterocyclyl containing at least one heteroatomselected from N, O or S, wherein said carbocyclyl and heterocyclyl mayeach be optionally substituted by one or more (e.g. 1, 2 or 3) R¹groups;

R¹ represents C₁₋₆alkyl or —C(═O)—O—C₁₋₆alkyl;

R³ represents hydroxyC₁₋₆alkyl, C₁₋₆alkyl substituted with R⁹, or

-   -   C₁₋₆alkyl substituted with —NR¹⁰R¹¹;

R^(3a) and R^(3b) are taken together to form ═O or ═CH—C₀₋₄alkylsubstituted with R^(3c);

R^(3c) is cyano;

R⁹ represents a 5 membered monocyclic heterocyclyl containing at leastone heteroatom selected from N, O or S, said 5 membered monocyclicheterocyclyl optionally substituted with —S(═O)₂—NR¹⁴R¹⁵;

R¹⁰ and R¹¹ each independently represent hydrogen or C₁₋₆alkyl;

R¹⁴ and R¹⁵ represent C₁₋₄alkyl;

n independently represents an integer equal to 1, 2, 3 or 4.

In one embodiment,

W is —N(R³)— or —C(R^(3a)R^(3b))—; in particular W is —N(R³)—; each R²is halogen or C₁₋₄alkoxy;

D represents a 5 to 6 ring membered monocyclic carbocyclyl or a 5 to 6ring membered monocyclic heterocyclyl containing at least one heteroatomselected from N or O,

wherein said carbocyclyl and heterocyclyl may each be optionallysubstituted by one R¹ group;

R¹ represents C₁₋₆alkyl or —C(═O)—O—C₁₋₆alkyl;

R³ represents hydroxyC₁₋₆alkyl, C₁₋₆alkyl substituted with R⁹, or

-   -   C₁₋₆alkyl substituted with —NR¹⁰R¹¹;

R^(3a) and R^(3b) are taken together to form ═O or ═CH—C₀₋₄alkylsubstituted with R^(3c);

R^(3c) is cyano;

R⁹ represents a 5 membered monocyclic heterocyclyl containing at leastone N-atom, said 5 membered monocyclic heterocyclyl optionallysubstituted with —S(═O)₂—NR¹⁴R¹⁵;

R¹⁰ and R¹¹ each independently represent hydrogen or C₁₋₆alkyl;

R¹⁴ and R¹⁵ represent C₁₋₄alkyl;

n independently represents an integer equal to 1, 2, 3 or 4.

In one embodiment,

W is —N(R³)— or —C(R^(3a)R^(3b))—; in particular W is —N(R³)—;

each R² is fluoro, chloro or methoxy;

D represents phenyl, pyridinyl, piperidinyl, tetrahydro-2H-pyranyl,pyrimidinyl or pyrazolyl, wherein pyrazolyl or piperidinyl areoptionally substituted with methyl or tert-butoxycarbonyl on theNH-group;

R³ represents 2-hydroxyethyl, 3-hydroxypropyl, —(CH₂)₂—NR¹⁰R¹¹,—(CH₂)₃—NR¹⁰R¹¹, or

-   -   methyl substituted with R⁹;

R^(3a) and R^(3b) are taken together to form ═O or ═CH—CN;

R⁹ represents imidazolyl optionally substituted with —S(═O)₂—NR¹⁴R¹⁵;

R¹⁰ and R¹¹ each independently represent hydrogen, methyl, ethyl orisopropyl;

R¹⁴ and R¹⁵ represent methyl;

n independently represents an integer equal to 1, 2, 3 or 4.

In one embodiment,

W is —N(R³)— or —C(R^(3a)R^(3b))—; in particular W is —N(R³)—;

each R² is halogen or C₁₋₄alkoxy;

D represents a 3 to 12 ring membered monocyclic or bicyclic carbocyclylor a 3 to 12 ring membered monocyclic or bicyclic heterocyclylcontaining at least one heteroatom selected from N, O or S, wherein saidcarbocyclyl and heterocyclyl may each be optionally substituted by oneor more (e.g. 1, 2 or 3) R¹ groups;

R¹ represents C₁₋₆alkyl or —C(═O)—O—C₁₋₆alkyl;

R³ represents hydroxyC₁₋₆alkyl optionally substituted with—O—C(═O)—C₁₋₆alkyl, substituted with R⁹ and optionally substituted with—O—C(═O)—C₁₋₆alkyl, or C₁₋₆alkyl substituted with —NR¹⁰R¹¹;

R^(3a) and R^(3b) are taken together to form ═O or ═CH—C₀₋₄alkylsubstituted with R^(3c);

R^(3c) is cyano;

R⁹ represents a 3 to 12 membered monocyclic or bicyclic heterocyclylcontaining at least one heteroatom selected from N, O or S, said 3 to 12membered monocyclic or bicyclic heterocyclyl optionally substituted with—S(═O)₂—NR¹⁴R¹⁵;

R¹⁰ and R¹¹ each independently represent hydrogen or C₁₋₆alkyl;

R¹⁴ and R¹⁵ each represent C₁₋₄alkyl;

n independently represents an integer equal to 1, 2, 3 or 4.

In one embodiment,

W is —N(R³)—;

each R² is fluoro or methoxy;

D represents piperidinyl or tetrahydro-2H-pyranyl, in particular4-piperidinyl or tetrahydro-2H-pyran-4-yl;

R³ represents C₁₋₄alkyl substituted with —NR¹⁰R¹¹;

R¹⁰ and R¹¹ each independently represent hydrogen, methyl, ethyl orisopropyl;

n independently represents an integer equal to 3 or 4.

In one embodiment,

W is —N(R³)—;

each R² is fluoro or methoxy;

D represents piperidinyl, tetrahydro-2H-pyranyl, or pyrazolyl, whereinpyrazolyl or piperidinyl are optionally substituted with methyl on theNH-group;

R³ represents —(CH₂)₂—NR¹⁰R¹¹, —(CH₂)₃—NR¹⁰R¹¹, or methyl substitutedwith R⁹;

R⁹ represents imidazolyl optionally substituted with —S(═O)₂—NR¹⁴R¹⁵;

R¹⁰ and R¹¹ each independently represent hydrogen, methyl, ethyl orisopropyl;

R¹⁴ and R¹⁵ represent methyl;

n independently represents an integer equal to 3 or 4.

In one embodiment, R³ represents hydroxyC₂₋₆alkyl, C₁₋₆alkyl substitutedwith R⁹, or

-   -   C₂₋₆alkyl substituted with —NR¹⁰R¹¹.

In one embodiment the compound of formula (I) is a compound of formula(Ia)

including any tautomeric or stereochemically isomeric form thereof;

wherein n, R¹, R² and R³ are as defined herein;

the N-oxides thereof, the pharmaceutically acceptable salts thereof orthe solvates thereof.

In one embodiment the compound of formula (I) is a compound of formula(Iab)

including any tautomeric or stereochemically isomeric form thereof;

wherein R³ and D are as defined herein;

the N-oxides thereof, the pharmaceutically acceptable salts thereof orthe solvates thereof.

In one embodiment the compound of formula (I) is a compound of formula(Iab)

including any tautomeric or stereochemically isomeric form thereof;

wherein R³ represents ethyl substituted with —NR¹⁰R¹¹;

R¹⁰ and R¹¹ each independently represent hydrogen, ethyl or isopropyl;

D represents pyrazolyl substituted with methyl;

the N-oxides thereof, the pharmaceutically acceptable salts thereof orthe solvates thereof.

In one embodiment, D represents phenyl, 3-pyridinyl, 4-pyridinyl,4-piperidinyl, tetrahydro-2H-pyran-4-yl, 5-pyrimidinyl or pyrazol-4-yl,wherein pyrazol-4-yl or 4-piperidinyl are optionally substituted withmethyl or tert-butoxycarbonyl on the NH-group.

In one embodiment, D represents a non-aromatic 5 or 6 ring memberedmonocyclic heterocyclyl containing at least one heteroatom selected fromN, O or S, wherein said heterocyclyl may each be optionally substitutedby one or more (e.g. 1, 2 or 3) R¹ groups.

In one embodiment, D represents a non-aromatic 6 ring memberedmonocyclic heterocyclyl containing at least one heteroatom selected fromN or O, wherein said heterocyclyl may each be optionally substituted byone or more (e.g. 1, 2 or 3) R¹ groups; in particular D isunsubstituted.

In another embodiment, D represents piperidinyl ortetrahydro-2H-pyranyl, in particular 4-piperidinyl ortetrahydro-2H-pyran-4-yl.

In one embodiment the compound of formula (I) is a compound of formula(Ia), including any tautomeric or stereochemically isomeric formthereof; wherein:

R¹ represents C₁₋₆alkyl;

R² represents C₁₋₄alkoxy, for example CH₃O—, or halo, for examplefluoro;

n=2 or 4; and

R³ represents hydroxyC₁₋₆alkyl, haloC₁₋₆alkyl or C₁₋₆alkyl substitutedwith R⁹;

the N-oxides thereof, the pharmaceutically acceptable salts thereof orthe solvates thereof.

In one embodiment, the compound of formula (I) is any one of thefollowing compounds

a N-oxide thereof, a pharmaceutically acceptable salt thereof or asolvate thereof; in particular a pharmaceutically acceptable saltthereof or a solvate thereof.

In one embodiment, the compound of formula (I) is any one of thefollowing compounds

In one embodiment, the compound of formula (I) is any one of thefollowing compounds

a N-oxide thereof, a pharmaceutically acceptable salt thereof or asolvate thereof; in particular a pharmaceutically acceptable saltthereof or a solvate thereof.

In one embodiment, the compound of formula (I) is any one of thefollowing compounds

For the avoidance of doubt, it is to be understood that each general andspecific preference, embodiment and example for one substituent may becombined, whenever possible, with each general and specific preference,embodiment and example for one or more, preferably, all othersubstituents as defined herein and that all such embodiments areembraced by this application.

Methods for the Preparation of Compounds of Formula (I)

In this section, as in all other sections of this application unless thecontext indicates otherwise, references to formula (I) also include allother sub-groups and examples thereof as defined herein.

In general, compounds of formula (I) wherein W is —N(R³)—, saidcompounds being represented by formula (Ib), can be prepared accordingto the following reaction Scheme 1.

In Scheme 1, the following reaction conditions apply:

1: in the presence of a suitable base, such as for example sodiumhydride or Cs₂CO₃, and a suitable solvent, such as for exampleN,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran oracetonitrile and wherein W₁ represents a suitable leaving group, such asfor example halo, e.g. bromo, chloro and the like, or O—S(═O)₂—CH₃, andR^(3d) represents optionally substituted C₁₋₆alkyl, such as for exampleCH₂—C₃H₅;

2: in the presence of a suitable base, such as for example sodiumhydride, Cs₂CO₃, or potassium hydroxide, and a suitable solvent, such asfor example N,N-dimethylformamide, N,N-dimethylacetamide or acetonitrileand wherein R′ represents optionally substituted C₁₋₄alkyl and R″represents hydrogen or optionally substituted C₁₋₄alkyl;

3: in the presence of a suitable phase transfer reagent such as forexample tetrabutylammonium bromide, a suitable base such as for examplepotassium hydroxide, and a suitable solvent such as for example2-methyltetrahydrofuran and water. When, an intermediate of formula (II)is reacting with an intermediate of formula W₁—C₁₋₆alkyl-Ncycle; thefollowing conditions can be applied: a suitable base, such as forexample sodium hydride, and a suitable solvent, such as for exampleN,N-dimethylformamide or N,N-dimethylacetamide.

4: in the presence of a suitable base, such as for example sodiumhydride, and a suitable solvent, e.g. N,N-dimethylformamide orN,N-dimethylacetamide, and wherein wherein P represents a suitableprotective group, such as for example C(═O)—O—C(CH₃)₃;

5: in the presence of a suitable acid, such as for example HCl ortrifluoroacetic acid, and a suitable solvent, such as for exampledichloromethane or an alcohol, e.g. methanol;

6: in the presence of a suitable base, such as for example sodiumhydride, and a suitable solvent, such as for exampleN,N-dimethylformamide or N,N-dimethylacetamide or tetrahydrofuran, andwherein W₂ represents a suitable leaving group, such as for examplehalo, e.g. bromo and wherein R^(x) and R^(y) represent C₁₋₄alkyl, andR^(z) represent C₁₋₄alkyl or phenyl, for instance R^(x) and R^(y)represent CH₃ and R^(z) represents C(CH₃)₃ or phenyl;

7: in the presence of a suitable solvent, such as for exampletetrahydrofuran. This type of reaction can also be performed in thepresence of a suitable acid, such as for example acetic acid or HCl, anda suitable solvent, such as for example dioxane;

8: in the presence of a suitable base, such as for example sodiumhydride, and a suitable solvent, such as for exampleN,N-dimethylformamide or N,N-dimethylacetamide and wherein W₃ representsa suitable leaving group, such as for example halo, e.g. bromo and thelike;

9: in the presence of a suitable acid, such as for example HCl, and asuitable solvent, such as for example an alcohol, e.g. methanol orisopropanol;

10: in the presence of a suitable base, such as for exampletriethylamine or diisopropylethanamine, and a suitable solvent, such asfor example dichloromethane or tetrahydrofuran.

During this reaction also a compound of formula (Ib-1-4) can be formed:

11: optionally in the presence of a suitable base, such as for exampletriethylamine, K₂CO₃, Na₂CO₃ or sodium hydride, and optionally asuitable solvent, such as for example acetonitrile, tetrahydrofuran,dioxane, N,N-dimethylformamide, 1-methyl-pyrrolidinone. This type ofreaction can also be performed with a suitable salt of NHR¹⁰R¹¹, e.g.HCl salt of NHR¹⁰R¹¹, or may be performed in the presence of potassiumiodide. In this way compounds wherein R³ represents iodoC₁₋₆alkyl can beobtained.

12: in the presence of a suitable solvent, such as for exampleacetonitrile, 1-methyl-2-pyrrolidinone, optionally in the presence ofpotassium iodide or a suitable base, such as for example Na₂CO₃, K₂CO₃or triethylamine. This reaction can also be performed with a suitablesalt of

which is a suitable nitrogen containing ring (unsubstituted orsubstituted) within the definition of R⁹;

13: in the presence of a suitable base, such as for example sodiumhydride, and a suitable solvent, such as for example dimethylacetamideand wherein P represents a suitable protective group, such as forexample C(═O)—O—C(CH₃)₃.

Intermediates of formula (II) used in the above Scheme 1 can be preparedaccording to the following reaction Scheme 2.

In Scheme 2 where W₁ represents a suitable leaving group such as forexample halo, e.g. bromo, chloro and the like, the following reactionconditions apply:

1: in the presence of triethyl orthoformate in a suitable solvent suchas for example toluene;

2: in the presence of a suitable catalyst, such as for examplechloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2′-4′-6′-tri-i-propyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl]palladium(II),a suitable base, such as for example cesium carbonate, in a suitablesolvent, such as for example toluene; or in the presence of a suitablecatalyst such as for example tris(dibenzylideneacetone)dipalladium(0)(Pd₂dba₃) in the presence of a suitable ligand, such as for example[1,1′-binaphthalene]-2,2′-diylbis[diphenylphosphine] (BINAP), and asuitable base, such as for example cesium carbonate, in a suitablesolvent, such as for example dioxane.

In general, compounds of formula (I) wherein W is —C(R^(3a)R^(3b))—,said compounds being represented by formula (Ic-1), can be preparedaccording to the following reaction Scheme 3.

In Scheme 3, where W₁ represents a suitable leaving group such as forexample halo, e.g. bromo, chloro and the like, the following reactionconditions apply:

1: in the presence of a suitable catalyst such as for example[1,1′-bis(diphenylphosphino-κP)ferrocene]dichloropalladium (PdCl₂dppf),and a suitable solvent such as for example tetrahydrofuran (THF);

2: in the presence of a suitable base, such as for example butyllithium, and a suitable solvent, such as for example THF, and R^(3d)represents optionally substituted C₁₋₆alkyl. This reaction can also beperformed with a protected form of the reactant, namely W₁—R^(3d)—Pwherein P is a suitable protective group, such as for example atert-butyldimethylsilyl group followed by a suitable deprotectionreaction, such as in the presence of a suitable desilylating reagentsuch as for example tetrabutylammonium fluoride, in a suitable solventsuch as for example tetrahydrofurane or such as in the presence of asuitable acid, such as for example HCl or trifluoroacetic acid (TFA),and a suitable solvent, such as for example an alcohol, e.g. methanol,or dichloromethane.

Compounds of formula (I) wherein W is —C(R^(3a)R^(3b))—, said compoundsbeing represented by formula (Ic-1), can also be prepared according tothe following reaction Scheme 4.

In Scheme 4, the following reaction conditions apply:

1,2,3: optionally in the presence of a suitable base, such as forexample triethylamine, isopropylamine, potassium carbonate, sodiumcarbonate or sodium hydride, and optionally a suitable solvent, such asfor example acetonitrile, tetrahydrofuran, N,N-dimethylformamide, asuitable alcohol, e.g. 1-butanol and the like, and wherein P representsa suitable protective group, such as for example —C(═O)—OC(CH₃)₃;

Step 1 can also be performed with a suitable salt of

which is a suitable nitrogen containing ring (unsubstituted orsubstituted) within the definition of R⁹.

4: in the presence of a suitable acid, such as for example HCl or TFA,and a suitable solvent, such as for example dichloromethane or analcohol, e.g. methanol.

Compounds of formula (I) wherein W is —C(R^(3a)R^(3b))—, said compoundsbeing represented by formula (Ic-1), (Id) or (Ie), can be preparedaccording to the following reaction Scheme 5.

In Scheme 5, the following reaction conditions apply:

1: in the presence of carbon monoxide, a suitable palladium catalyst,such as for example palladium(II) acetate (Pd(OAc)₂), a suitable ligand,such as for example tricyclohexylphosphine, a suitable base, such as forexample triethylamine in a suitable solvent, such as for example toluene

2: in a suitable solvent such as for example toluene

3: in the presence of a suitable lewis acid, such as for exampletrimethylaluminum, and a suitable solvent, such as for example toluene;

4: in the presence of a suitable catalyst, such as for exampletetrakis(triphenylphosphine)palladium (Pd(PPh₃)₄), a suitable solvent,such as for example toluene and a suitable acid such as hydrogenchloride

5: in the presence of a suitable solvent, such as for exampletetrahydrofuran.

A compound of formula (Ie-2a)

can be prepared by an analogous reaction protocol as used for thesynthesis of an intermediate of formula (XIII).

Compounds of formula (I) wherein W is —C(R^(3a)R^(3b))—, said compoundsbeing represented by formula (Ic-2) can be prepared according to thefollowing reaction Scheme 6.

In Scheme 6, the following reaction conditions apply:

1: in the presence of a suitable reducing agent, such as for examplesodium borohydride and in the presence of a suitable solvent, such asfor example methanol;

2: in the presence of a suitable base, such as for example sodiumhydride, and a suitable solvent, such as for exampleN,N-dimethylformamide or N,N-dimethylacetamide, and wherein R^(x) andR^(y) represents C₁₋₄alkyl, and wherein R^(z) represents C₁₋₄alkyl orphenyl, for instance R^(x) and R^(y) represent CH₃ and R^(z) representsC(CH₃)₃ or phenyl, and wherein W₂ represents a suitable leaving group,such as for example halo, e.g. bromo;

3: in the presence of a suitable acid, such as for example TFA, and asuitable solvent, such as for example tetrahydrofuran. This reaction canalso be performed with tetrabutyl ammonium fluoride in the presence of asuitable solvent such as for example tetrahydrofuran.

Compounds of formula (Ib) wherein R³ represents optionally substitutedC₂₋₆alkynyl, said compounds being represented by formula (Ib-2), can beprepared according to reaction Scheme 7.

In Scheme 7, the following reaction conditions apply:

in the presence of a suitable base, such as for example NaH, and asuitable solvent, such as for example N,N-dimethylformamide and whereinR^(3e) represents optionally substituted C₂₋₆alkynyl and W₆ represents asuitable leaving group such as for example halo, e.g. chloro, orO—S(═O)₂—CH₃, The intermediate W₆—R^(3e) wherein W₆ representsO—S(═O)₂—CH₃, can be prepared by reacting the corresponding alcoholderivative with methanesulfonyl chloride in the presence of a suitablebase, such as for example triethylamine or 4-dimethylaminopyridine, anda suitable solvent, such as for example dichloromethane.

Compounds of formula (Ib-2), wherein R^(3e) represents C₂₋₆alkynylsubstituted with hydroxyl, said compounds being represented by formula(Ib-2-1), can be prepared according to the following reaction Scheme 8.

In Scheme 8, the following reaction conditions apply:

1: in the presence of a suitable base, such as for example NaH, and asuitable solvent, such as for example N,N-dimethylformamide, and whereR^(x), R^(y) and R^(z) are as defined hereinabove;

2: in the presence of a suitable acid, such as for exampletrifluoroacetic acid, and a suitable solvent, such as for exampletetrahydrofuran. This reaction can also be performed with tetrabutylammonium fluoride in the presence of a suitable solvent such as forexample tetrahydrofuran.

Alternatively, instead of an intermediate of formula (XVI),halo-C₂₋₆alkynyl-O—Si(R^(x))(R^(y))(R^(z)) can also be used.

Compounds of formula (Ib-2), wherein R^(3e) represents C₂₋₆alkynyl, saidcompounds being represented by formula (Ib-2-2), can be preparedaccording to the following reaction Scheme 9.

In Scheme 9, the following reaction conditions apply:

1: in the presence of a suitable base, such as for example NaH, and asuitable solvent, such as for example N,N-dimethylformamide, and whereinW₇ is a suitable leaving group, such as for example halogen;

2: in the presence of a suitable base, such as for example K₂CO₃, and asuitable solvent, such as for example an alcohol, e.g. methanol and thelike.

Compounds of formula (Ib), wherein R³ represents ethyl substituted with—P(═O)(OC₁₋₆alkyl)₂, said compounds being represented by formula(Ib-1-7), can be prepared according to the following reaction Scheme 10.

In Scheme 10, the following reaction conditions apply:

in the presence of a suitable catalyst, such as for exampletri-N-butylphosphine, and a suitable solvent, such as for exampleacetonitrile.

Intermediates of formula (IV′) wherein D is a ring moiety containing anitrogen atom, as represented in Scheme 11, can be further reactedaccording to the following reaction Scheme 11. In Scheme 11, R^(6b) isdefined as a 4 to 7-membered monocyclic heterocyclyl which is attachedto the remainder of the molecule via a N-atom, and which optionallycontains at least one additional heteroatom selected from N, O or S.

In Scheme 11, the D′N moiety represents a -D moiety wherein the D ringmoiety contains a nitrogen atom, the following reaction conditionsapply:

1: by reaction with W₈—C₁₋₆alkyl-halo wherein W₈ represents a suitableleaving group, such as for example halo, e.g. chloro, in the presence ofa suitable base, such as for example NaH, and a suitable solvent, suchas for example N,N-dimethylformamide;

2: by reaction with R^(6b) in the presence of a suitable base, such asfor example K₂CO₃, and a suitable solvent, such as for exampleacetonitrile;

3: when in an intermediate of formula (IV′-c) the R^(6b) carries ahydroxyl group as in an intermediate of formula (IV′-c-1), then saidhydroxyl group can be protected by a suitable protective group P, suchas for example —O—C(═O)—C₁₋₆alkyl, by reaction with C₁₋₆alkyl-C(═O)—W₉wherein W₉ represents a suitable leaving group, such as for examplehalo, e.g. chloro, in the presence of a suitable base, such as forexample triethylamine, 4-dimethylaminopyridine, and a suitable solvent,such as for example dichloromethane;

4: by reaction with tetrabutylammonium fluoride (TBAF) in the presenceof a suitable solvent, such as for example tetrahydrofuran;

5: by reaction with methane sulfonyl chloride in the presence of asuitable base, such as for example triethylamine, and a suitablesolvent, such as for example dichloromethane, and wherein R^(u)represents SO₂CH₃;

6: by reaction with an intermediate of formula NHR¹⁰R¹¹ in a suitablesolvent, such as for example acetonitrile;

7: in the presence of a suitable base, such as for example K₂CO₃, and asuitable solvent, such as for example an alcohol, e.g. methanol and thelike. It is considered to be within the knowledge of the person skilledin the art to recognize for which other D ring moieties the describedreactions also apply.

Intermediates of formula (IV′) and (XX) can also be reacted to preparecompounds of the present invention according to the reaction schemes aspresented in Scheme 1. It is considered to be within the knowledge ofthe skilled person to recognize in which condition and for whichdefinitions of R¹ on the D ring moiety a protective group may beappropriate for the reactions to be carried out. For instance, ahydroxyl group within the definition of R¹ may be protected with a tert.butyldimethylsilyl moiety; a NH group within the definition of R¹ may beprotected with a C(═O)—O—C(CH₃)₃ group.

It is also considered to be within the knowledge of the skilled personto recognize appropriate deprotection reactions.

Compounds of formula (Ib) wherein R³ is C₁₋₆alkyl substituted with3,3-dimethyl-morpholine can be prepared according to the below reactionScheme 12.

In Scheme 12, the following reaction conditions apply:

1: reaction with 2-amino-2-methyl-1-propanol in the presence of asuitable base, such as for example NaH and in the presence of a suitablesolvent, such as for example N, N-dimethylformamide;

2: reaction with for instance di-tert-butyl dicarbonate in the presenceof a suitable solvent, such as for example dioxane, and a suitable base,such as for example NaHCO₃, and wherein P is a suitable protecting groupP, such as for example —C(═O)—O—C(CH₃)₃;

3: reaction with methanesulfonyl chloride in the presence of a suitablesolvent, such as for example dichloromethane, and a suitable base, suchas for example triethylamine;

4: reaction with a suitable acid, such as for example trifluoroaceticacid, in the presence of a suitable solvent, such as for exampledichloromethane;

5: in the presence of a suitable base, such as for exampleN,N-diisopropylethylamine and triethylamine, and a suitable solvent,such as for example an alcohol, e.g. methanol. Compounds of formula (Ib)wherein R³ is C₁₋₆alkyl substituted with 5-amino-1,3,4-oxadiazolyl canbe prepared according to the below reaction Scheme 13.

In Scheme 13, the following reaction conditions apply:

1: in the presence of a suitable solvent, such as for example analcohol, e.g. ethanol;

2: in the presence of a suitable base, such as for example NaHCO₃, and asuitable solvent, such as for example water or dioxane, and wherein W₁₀represents a suitable leaving group, such as for example halo, e.g.bromo.

It is considered to be within the knowledge of the person skilled in theart to recognize in which condition and on which part of the molecule aprotective group may be appropriate. For instance, protective group onthe R¹ substituent or on the D moiety, or protective group on the R³substituent or on the R² substituent or combinations thereof. Theskilled person is also considered to be able to recognize the mostfeasible protective group, such as for example C(═O)—O—C₁₋₄alkyl or

or O—Si(CH₃)₂(C(CH₃)₃) or —CH₂—O—CH₂CH₂—O—CH₃. The skilled person isalso considered to be able to recognize the most feasible deprotectionreaction conditions, such as for example suitable acids, e.g.trifluoroacetic acid, hydrochloric acid, or suitable salts, such as forexample tetrabutylammonium fluoride (TBAF).

The skilled person is also considered to be able to recognize that whenR¹ represents C(═O)-morpholinyl, said R¹ can be prepared fromC(═O)—NH—CH₂—CH₂—O—CH₂—CH₂—O—SO₂-4-methylphenyl, in the presence ofsodium hydride, and a suitable solvent, such as for exampleN,N-dimethylformamide. Or that when R¹ represents NH—C(═O)-morpholinyl,said R¹ can be prepared from NH—C(═O)—O—C(CH₃)₃ in the presence ofmorpholine, and a suitable solvent, such as for example1-methyl-2-pyrrolidinone. Or that when R¹ represents hydroxylC₁₋₆alkyl,e.g. CH₂—CH₂—OH, said R¹ can be prepared from the correspondingalkoxycarbonyl intermediate, e.g. CH₂—C(═O)—O—CH₂—CH₃, in the presenceof Dibal-H 1M in hexane, and a suitable solvent, such as for exampletetrahydrofuran.

The present invention also comprises deuterated compounds. Thesedeuterated compounds may be prepared by using the appropriate deuteratedintermediates during the synthesis process. For instance the belowintermediate

can be converted into the below intermediate

by reaction with iodomethane-D3 in the presence of a suitable base, suchas for example cesium carbonate, and a suitable solvent, such as forexample acetonitrile.

The compounds of formula (I) may also be converted into each other viaart-known reactions or functional group transformations.

For instance, compounds of formula (I) wherein R¹ representstetrahydropyranyl can be converted into a compound of formula (I)wherein R¹ represents hydrogen, by reaction with a suitable acid, suchas for example HCl or trifluoroacetic acid, in the presence of asuitable solvent, such as for example dichloromethane, dioxane, or analcohol, e.g. methanol, isopropanol and the like.

Compounds of formula (I) wherein R¹ or R³ represent monohaloalkyl, canbe converted into a compound of formula (I) wherein R¹ or R³ representC₁₋₆alkyl substituted with a ring moiety as defined hereinabove andlinked to the C₁₋₆alkyl moiety by the nitrogen atom, by reaction with asuitable ring moiety optionally in the presence of a suitable base, suchas for example triethylamine or K₂CO₃ or sodium hydride, and optionallyin the presence of a suitable solvent, such as for example acetonitrile,N,N-dimethylformamide or 1-methyl-2-pyrrolidinone.

Compounds of formula (I) wherein R¹ or R³ represents C₁₋₆alkyl-OH, canbe converted into a compound of formula (I) wherein R¹ or R³ representC₁₋₆alkyl-F by reaction with diethylaminosulfur trifluoride in thepresence of a suitable solvent, such as for example dichloromethane andin the presence of catalytic amounts of an alcohol, such as for exampleethanol. Likewise, a compound of formula (I) wherein R¹ or R³ representC₁₋₆alkyl substituted with R⁶ or R⁹ wherein said R⁶ or R⁹ is substitutedwith OH, can be converted into a compound of formula (I) wherein R¹ orR³ represent C₁₋₆alkyl substituted with R⁶ or R⁹ wherein said R⁶ or R⁹is substituted with F, by reaction with diethylaminosulfur trifluoridein the presence of a suitable solvent, such as for exampledichloromethane.

Compounds of formula (I) wherein R¹ or R³ represent C₁₋₆alkylsubstituted with R⁶ or R⁹ wherein said R⁶ or R⁹ is substituted with—C(═O)—O—C₁₋₆alkyl, can be converted into a compound of formula (I)wherein R¹ or R³ represent C₁₋₆alkyl substituted with R⁶ or R⁹ whereinsaid R⁶ or R⁹ is substituted with —CH₂—OH, by reaction with a suitablereducing agent such as for example LiAlH₄, in the presence of a suitablesolvent, such as for example tetrahydrofuran.

Compounds of formula (I) wherein R³ represents C₁₋₆alkyl substitutedwith 1,3-dioxo-2H-isoindol-2-yl, can be converted into a compound offormula (I) wherein R³ represents C₁₋₆alkyl substituted with amino, byreaction with hydrazine monohydrate in the presence of a suitablesolvent, such as for example an alcohol, e.g. ethanol.

Compounds of formula (I) wherein R¹ or R³ represent C₁₋₆alkylsubstituted with amino, can be converted into a compound of formula (I)wherein R¹ or R³ represents C₁₋₆alkyl substituted with—NH—S(═O)₂—C₁₋₆alkyl, by reaction with Cl—S(═O)₂—C₁₋₆alkyl in thepresence of a suitable base, such as for example triethylamine, and asuitable solvent, such as for example dichloromethane.

Compounds of formula (I) wherein R¹ or R³ represents C₁₋₆alkylsubstituted with halo, can be converted into a compound of formula (I)wherein R¹ or R³ represent C₁₋₆alkyl substituted with NR⁴R⁵ or NR¹⁰R¹¹,by reaction with NHR⁴R⁵ or NHR¹⁰R¹¹, either using such amino in largeexcess or in the presence of a suitable base, such as for example K₂CO₃,and a suitable solvent, such as for example acetonitrile,N,N-dimethylacetamide or 1-methyl-pyrrolidinone.

Compounds of formula (I) wherein R¹ represents hydrogen, can beconverted into a compound of formula (I) wherein R¹ representspolyhaloC₁₋₆alkyl or polyhydroxyC₁₋₆alkyl or C₁₋₆alkyl or—S(═O)₂—NR¹⁴R¹⁵ or —S(═O)₂—C₁₋₆alkyl, by reaction withpolyhaloC₁₋₆alkyl-W or polyhydroxyC₁₋₆alkyl-W or C₁₋₆alkyl-W orW—S(═O)₂—NR¹⁴R¹⁵ or W—S(═O)₂—C₁₋₆alkyl, wherein W represents a suitableleaving group, such as for example halo, e.g. bromo and the like, in thepresence of a suitable base, such as for example sodium hydride or K₂CO₃or triethylamine or 4-dimethylamino-pyridine or diisopropylamine, and asuitable solvent, such as for example N,N-dimethylformamide oracetonitrile or dichloromethane. Compounds of formula (I) wherein R¹represents hydrogen can also be converted into a compound of formula (I)wherein R¹ represents C₁₋₆alkyl-OH, by reaction withW—C₁₋₆alkyl-O—Si(CH₃)₂(C(CH₃)₃) in the presence of a suitable base, suchas for example sodium hydride, and a suitable solvent, such as forexample N,N-dimethylformamide. The skilled person will realize that thisstep is followed by reaction with a suitable acid, such as for exampletrifluoroacetic acid, in a suitable solvent, such as for exampletetrahydrofuran, or by reaction with tetrabutyl ammonium fluoride in thepresence of a suitable solvent, such as for example tetrahydrofuran.

Compounds of formula (I) wherein R¹ represents hydrogen, can also beconverted into compound of formula (I) wherein R¹ represents ethylsubstituted with —S(═O)₂—C₁₋₆alkyl, by reaction withC₁₋₆alkyl-vinylsulfone, in the presence of a suitable base, such as forexample triethylamine, and a suitable solvent, such as for example analcohol, e.g. methanol or by reaction with C₁₋₆alkyl-2-bromoethylsulfonein the presence of a suitable deprotonating agent, such as for exampleNaH, and a suitable solvent, such as for example dimethyformamide.

Compounds of formula (I) wherein R¹ represents hydrogen can also beconverted into a compound of formula (I) wherein R¹ represents

by reaction with

in the presence of a suitable base, such as for example sodium hydride,and a suitable solvent, such as for example N,N-dimethylformamide,wherein

represents a suitable nitrogen containing ring within the definition ofR⁶.

Compounds of formula (I) wherein R¹ represents C₁₋₆alkyl substitutedwith R⁶ wherein said R⁶ is substituted with —C(═O)—O—C₁₋₆alkyl orS(═O)₂—NR¹⁴R¹⁵ or wherein R³ represents C₁₋₆alkyl substituted with R⁹wherein said R⁹ is substituted with —C(═O)—O—C₁₋₆alkyl orS(═O)₂—NR¹⁴R¹⁵, can be converted into a compound of formula (I) whereinthe R⁶ or R⁹ is unsubstituted, by reaction with a suitable acid, such asfor example HCl and a suitable solvent, such as for example dioxane,acetonitrile or an alcohol, e.g. isopropylalcohol.

Compounds of formula (I) wherein R¹ represents C₁₋₆alkyl substitutedwith R⁶ wherein said R⁶ is a ring moiety comprising a nitrogen atomwhich is substituted with CH₂—OH or wherein R³ represents C₁₋₆alkylsubstituted with R⁹ wherein said R⁹ is a ring moiety comprising anitrogen atom which is substituted with CH₂—OH, can be converted into acompound of formula (I) wherein the R⁶ or R⁹ is unsubstituted, byreaction with sodium hydroxide, in the presence of a suitable solvent,such as for example tetrahydrofuran. Compounds of formula (I) wherein R¹represents C₁₋₆alkyl substituted with R⁶ or R³ represents C₁₋₆alkylsubstituted with R⁹, wherein said R⁶ or said R⁹ is unsubstituted, can beconverted into a compound of formula (I) wherein said R⁶ or said R⁹ issubstituted with C₁₋₆alkyl, by reaction with W—C₁₋₆alkyl wherein W is asdefined above, in the presence of a suitable base. Such as for examplesodium hydride, and a suitable solvent, such as for exampleN,N-dimethylformamide.

Compounds of formula (I) wherein R¹ or R³ represent hydroxyC₁₋₆alkyl,can be converted into the corresponding carbonyl compound, by reactionwith dess-Martin-periodinane, in the presence of a suitable solvent,such as for example dichloromethane.

Compounds of formula (I) wherein R¹ represents C₁₋₆alkyl substitutedwith R⁶ or R³ represents C₁₋₆alkyl substituted with R⁹, wherein said R⁶or said R⁹ is substituted with C₁₋₆alkyl-halo, can be converted into acompound of formula (I) wherein said R⁶ or said R⁹ is substituted withC₁₋₆alkyl-CN, by reaction with sodium cyanide, in the presence of asuitable solvent, such as for example water or an alcohol, e.g. ethanol.

Compounds of formula (I) wherein R¹ represents C₁₋₆alkyl substitutedwith R⁶ wherein said R⁶ is unsubstituted or wherein R³ representsC₁₋₆alkyl substituted with R⁹ wherein said R⁹ is unsubstituted, can beconverted into a compound of formula (I) wherein R⁶ or R⁹ is substitutedwith CH₃ or CH(CH₃)₂, by reaction with formaldehyde or acetone andNaBH₃CN, in the presence of a suitable solvent, such as for exampletetrahydrofuran or an alcohol, e.g. methanol.

Compounds of formula (I) wherein R¹ contains a R⁶ substituentsubstituted with OH or wherein R³ contains a R⁹ substituent substitutedwith OH, can be converted into a compound of formula (I) wherein the R⁶or R⁹ substituent is substituted with C₁₋₆alkyloxy, by reaction withW—C₁₋₆alkyl, in the presence of a suitable base, such as for examplesodium hydride, and a suitable solvent, such as for exampleN,N-dimethylformamide. Compounds of formula (I) wherein R¹ contains a R⁶substituent substituted with C₁₋₆alkyloxy or wherein R³ contains a R⁹substituent substituted with C₁₋₆alkyloxy, can be converted into acompound of formula (I) wherein the R⁶ or R⁹ substituent is substitutedwith OH by reaction with a suitable acid, such as for examplehydrochloric acid. Compounds of formula (I) wherein R¹ contains a R⁶substituent substituted with halo or wherein R³ contains a R⁹substituent substituted with halo can be converted into a compound offormula (I) wherein the R⁶ or R⁹ substituent is substituted with NR¹⁴R¹⁵by reaction with NHR¹⁴R¹⁵ in a suitable solvent, such as for example1-methyl-pyrrolidinone. Compounds of formula (I) wherein R³ representsC₁₋₆alkyl substituted with —C(═O)—O—C₁₋₆alkyl, can be converted into acompound of formula (I) wherein R³ represents C₁₋₆alkyl substituted withCOOH, by reaction with LiOH in the presence of a suitable solvent, suchas for example tetrahydrofuran. Said compounds of formula (I) wherein R³represents C₁₋₆alkyl substituted with COOH, can be converted into acompound of formula (I) wherein R³ represents C₁₋₆alkyl substituted withC(═O)—NH₂ or —C(═O)—NHCH₃ or —C(═O)NR¹⁰R¹¹, by reaction withNH(Si(CH₃)₃)₂ or MeNH₃ ⁺Cl⁻ or NHR¹⁰R¹¹ in the presence of suitablepeptide coupling reagents such as for example1-(3-dimethylaminopropyl)-3-ethylcarbodiimide HCl and1-hydroxybenzotriazole, a suitable base, such as for exampletriethylamine and a suitable solvent such as for example dichloromethaneor N,N-dimethylformamide.

Compounds of formula (I) wherein R³ represents C₁₋₆alkyl substitutedwith —C(═O)—O—C₁₋₆alkyl, can also be converted into a compound offormula (I) wherein R³ represents C₁₋₆alkyl substituted with4,5-dihydro-imidazol-2-yl, by reaction under N₂ with ethylenediamine andtrimethylaluminium in the presence of a suitable solvent, such as forexample toluene and heptane. Compounds of formula (I) wherein R³represents C₁₋₆alkyl substituted with COOH, can also be converted into acompound of formula (I) wherein R³ represents C₁₋₆alkyl substituted with—C(═O)—N(CH₃)(OCH₃) by reaction with dimethylhydroxylamine, in thepresence of carbonyldiimidazole and a suitable solvent, such as forexample dichloromethane.

Compounds of formula (I) wherein R³ represents C₁₋₆alkyl substitutedwith

can be converted into a compound of formula (I) wherein R³ representsC₁₋₆alkyl substituted with 2 OH's, by reaction with a suitable acid,such as for example trifluoroacetic acid, and a suitable solvent, suchas for example dioxane or water. These compounds of formula (I) whereinR³ represents C₁₋₆alkyl substituted with

can also be converted into a compound of formula (I) wherein R³represents C₁₋₆alkyl substituted with OH and NR¹⁰R¹¹, by reaction withNH₂R¹⁰R¹¹ optionally in salt form, such as for example NHR¹⁰R¹¹⁺Cl⁻,optionally in the presence of a suitable base, such as for examplesodium hydride or Na₂CO₃ or triethylamine, a suitable additive such asfor example KI, and in the presence of a suitable solvent, such as forexample N,N-dimethylformamide or an alcohol, e.g. 1-butanol or ethanol.

Compounds of formula (I) wherein R³ represents C₁₋₃alkyl substitutedwith —C(═O)—O—C₁₋₆alkyl, can be converted into a compound of formula (I)wherein R³ represents C₁₋₃alkyl substituted with —C(CH₃)₂—OH, byreaction with iodomethane and Mg powder, in the presence of a suitablesolvent, such as for example diethylether or tetrahydrofuran. Compoundsof formula (I) wherein R³ represents C₁₋₅alkyl substituted with—C(═O)—O—C₁₋₆alkyl, can be converted into a compound of formula (I)wherein R³ represents C₁₋₆alkyl substituted with OH, by reaction with asuitable reducing agent such as for example LiAlH₄, in a suitablesolvent, such as for example tetrahydrofuran.

Compounds of formula (I) wherein R³ represents C₁₋₅alkyl substitutedwith OH, can be converted into a compound of formula (I) wherein R³represents C₁₋₅alkyl substituted with —O—C(═O)—C₁₋₆alkyl by reactionwith Cl—C(═O)—C₁₋₆alkyl in the presence of a suitable base, such as forexample NaH, and a suitable solvent, such as for exampletetrahydrofuran.

Compounds of formula (I) wherein R³ represents CH₂—CH═CH₂, can beconverted into a compound of formula (I) wherein R³ representsCH₂—CHOH—CH₂—OH, by reaction with potassium permanganate, and a suitablesolvent, such as for example acetone or water. Compounds of formula (I)wherein R³ represents C₁₋₆alkyl substituted with —C(═O)—C₁₋₄alkyl, canbe converted into a compound of formula (I) wherein R³ representsC₁₋₆alkyl substituted with —C(C₁₋₄alkyl)=N—OH, by reaction withhydroxylamine, in the presence of a suitable base, such as for examplepyridine, and a suitable solvent, such as for example an alcohol, e.g.ethanol.

Compounds of formula (I) wherein R³ represents C₁₋₆alkyl substitutedwith NH₂, can be converted into a compound of formula (I) wherein R³represents C₁₋₆alkyl substituted with —NH—C(═O)—R⁶ or with—NH—C(═O)—C₁₋₆alkyl or with —NH—C(═O)-polyhydroxyC₁₋₆alkyl or with—NH—C(═O)-polyhaloC₁₋₆alkyl or with—NH—C(═O)-polyhydroxypolyhaloC₁₋₆alkyl, by reaction with thecorresponding COOH analogue, e.g. R⁶—COOH or CF₃—C(CH₃)(OH)—COOH and thelike, in the presence of suitable peptide coupling reagents such as1-hydroxy-benzotriazole and 1-(3-dimethylamino)propyl)carbodiimideoptionally in the presence of a suitable base, such as for exampletriethylamine. Said compounds of formula (I) wherein R³ representsC₁₋₆alkyl substituted with NH₂, can also be converted into a compound offormula (I) wherein R³ represents C₁₋₆alkyl substituted withNH—C(═O)—CF₃, by reaction with trifluoroacetic anhydride, in thepresence of a suitable base, such as for example triethylamine, and asuitable solvent, such as for example tetrahydrofuran. Said compounds offormula (I) wherein R³ represents C₁₋₆alkyl substituted with NH₂, canalso be converted into a compound of formula (I) wherein R³ representsC₁₋₆alkyl substituted with NH-polyhaloC₁₋₆alkyl, e.g. NH—CH₂—CH₂—F, byreaction with polyhaloC₁₋₆alkyl-W, with W as defined above, e.g.iodo-2-fluoroethane, in the presence of a suitable base, such as forexample K₂CO₃, and a suitable solvent, such as for exampleN,N-dimethylformamide or dioxane.

Compounds of formula (I) wherein R³ represents C₁₋₆alkyl substitutedwith cyano, can be converted into a compound of formula (I) wherein R³represents C₁₋₆alkyl substituted with tetrazolyl by reaction with sodiumazide, and NH₄ ⁺Cl⁻ in the presence of a suitable solvent, such as forexample N,N-dimethylformamide.

Compounds of formula (I) wherein R³ represents —CH₂—C≡CH can beconverted into a compound of formula (I) wherein R³ represents

by reaction with ethyl azidoacetate in the presence of CuI and asuitable base, such as for example diisopropylamine, and a suitablesolvent, such as for example tetrahydrofuran. Compounds of formula (I)wherein R³ represents —CH2-C≡CH can be converted into a compound offormula (I) wherein R³ represents

by reaction with sodium azide and formaldehyde, in the presence of asuitable catalyst, such as for example CuSO₄ and sodium L ascorbate, asuitable acid, such as for example acetic acid, and a suitable solvent,such as for example dioxane.

Compounds of formula (I) wherein R³ represent C₂₋₆alkynyl, can beconverted into a compound of formula (I) wherein R³ representsC₂₋₆alkynyl substituted with R⁹, by reaction with W—R⁹ wherein W is asdefined above, in the presence of a suitable catalyst, such as forexample dichlorobis(triphenylphosphine)palladium, a suitable co-catalystsuch as CuI, a suitable base, such as for example triethylamine, and asuitable solvent, such as for example dimethylsulfoxide.

Compounds of formula (I) wherein R³ comprises R⁹ substituted with halo,can be converted into a compound of formula (I) wherein R³ comprises R⁹substituted with —NR¹⁴R¹⁵ by reaction with NHR¹⁴R¹⁵ in the presence of asuitable solvent, such as for example 1-methyl-2-pyrrolidinone.

Compounds of formula (I) wherein R³ comprises C₂₋₆alkynyl, can behydrogenated into a compound of formula (I) wherein R³ comprisesC₂₋₆alkyl in the presence of a suitable catalyst, such as for examplepalladium on charcoal, and a suitable solvent, such as for exampleethylacetate.

Compounds of formula (I) wherein R³ comprises C₂₋₆alkynyl, can behydrogenated into a compound of formula (I) wherein R³ comprisesC₂₋₆alkenyl in the presence of a suitable catalyst, such as for exampleLindlar catalyst, and a suitable solvent, such as for exampleethylacetate.

Compounds of formula (I) wherein R³ represents C₁₋₆alkyl substitutedwith —P(═O)(OC₁₋₆alkyl)₂ can be converted into a compound of formula (I)wherein R³ represents C₁₋₆alkyl substituted with —P(═O)(OH)₂ by reactionwith bromotrimethylsilane in the presence of a suitable solvent, such asfor example dichloromethane.

Compounds of formula (I) wherein the R⁹ substituent is substituted with═O, can be converted into the corresponding reduced R⁹ substituent byreaction with a suitable reducing agent, such as for example NaBH₄ in asuitable solvent, such as for example tetrahydrofuran.

Compounds of formula (I) wherein R³ comprises —NHR¹⁰ can be convertedinto a compound of formula (I) wherein R³ comprises—NR¹⁰—(C═O)-optionally substituted C₁₋₆alkyl, by reaction with thecorresponding W—(C═O)-optionally substituted C₁₋₆alkyl wherein Wrepresents a suitable leaving group, such as for example halo, e.g.chloro and the like, in the presence of a suitable base, such as forexample triethylamine, and a suitable solvent, such as for exampleacetonitrile.

Compounds of formula (I) wherein R³ represents C₁₋₆alkyl substitutedwith NR¹⁰(benzyl) can be converted into a compound of formula (I)wherein R³ represents C₁₋₆alkyl substituted with NHR¹⁰, by reaction with1-chloroethylchloroformate in the presence of a suitable solvent, suchas for example dichloromethane

Compounds of formula (I) wherein R¹ represents unsubstituted piperidine,can be converted into a compound of formula (I) wherein R¹ represents1-methyl-piperidine, by reaction with iodomethane in the presence of asuitable base, such as for example potassium carbonate, and a suitablesolvent, such as for example acetonitrile.

Compounds of formula (I) wherein R¹ represents hydrogen can be convertedinto a compound of formula (I) wherein R¹ represents optionallysubstituted C₁₋₆alkyl, by reaction with optionally substitutedC₁₋₆alkyl-W wherein W represents a suitable leaving group, such as forexample halo, e.g. bromo and the like, in the presence of a suitablebase, such as for example potassium carbonate, and a suitable solvent,such as for example acetonitrile.

Compounds of formula (I) wherein R² represents halo, e.g. bromo, can beconverted into a compound of formula (I) wherein R² represents cyano, byreaction with zinc cyanide, in the presence of a suitable catalyst, suchas for example Pd₂(dba)₃ and a suitable ligand, such as for example1,1-bis(diphenylphosphino)ferrocene, in the presence of a suitablesolvent, such as for example N,N-dimethylformamide.

Said R² substituent being cyano can be converted into CH₂—NH₂ byhydrogenation in the presence of NH₃ and Nickel.

Compounds of formula (I) wherein R² represents OCH₃ can be convertedinto a compounds of formula (I) wherein R² represents OH by reactionwith boron tribromide in the presence of a suitable solvent, such as forexample dichloromethane.

Compounds of formula (I) wherein R² represents OH can be converted intoa compounds of formula (I) wherein R² represents OCH₃ by reaction withmethyl iodine in the presence of a suitable base, such as for examplepotassium carbonate, and a suitable solvent, such as for exampleN,N-dimethylformamide.

Compounds of formula (I) wherein R² represents hydrogen, can beconverted into a compound of formula (I) wherein R² represents —CHOH—CF₃by reaction with trifluoroacetaldehyde methyl hemiketal.

It is understood to be within the knowledge of the skilled man torecognize the above conversion reactions also applicable to the R^(3a)substituent.

A further aspect of the invention is a process for the preparation of acompound of formula (I) as defined herein, which process comprises:

(i) reacting an intermediate of formula

with

(a) W₁—R^(3d) in the presence of a suitable base, such as for examplesodium hydride or Cs₂CO₃, and a suitable solvent, such as for exampleN,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran oracetonitrile and wherein W₁ represents a suitable leaving group, such asfor example halo, e.g. bromo, chloro and the like, or O—S(═O)₂—CH₃, andR^(3d) represents optionally substituted C₁₋₆alkyl, such as for exampleCH₂—C₃H₅; or

(b)

in the presence of a suitable base, such as for example sodium hydride,Cs₂CO₃, or potassium hydroxide, and a suitable solvent, such as forexample N,N-dimethylformamide, N,N-dimethylacetamide or acetonitrile andwherein R′ represents optionally substituted C₁₋₄alkyl and R″ representshydrogen or optionally substituted C₁₋₄alkyl; or

(c) W₁—C₁₋₆alky-NHR¹⁰ in the presence of a suitable phase transferreagent such as for example tetrabutylammonium bromide, a suitable basesuch as for example potassium hydroxide, and a suitable solvent such asfor example 2-methyltetrahydrofuran and water;

(d) W₁—C₁₋₆alkyl-Ncycle in the presence of a suitable base, such as forexample sodium hydride, and a suitable solvent, such as for exampleN,N-dimethylformamide or N, N-dimethylacetamide;

(ii) deprotecting an intermediate of formula

in the presence of a suitable acid, such as for example HCl ortrifluoroacetic acid, and a suitable solvent, such as for exampledichloromethane or an alcohol, e.g. methanol;

(iii) reacting an intermediate of formula

wherein R^(x) and R^(y) represent C₁₋₄alkyl, and R^(z) representC₁₋₄alkyl or phenyl, for instance R^(x) and R^(y) represent CH₃ andR^(z) represents C(CH₃)₃ or phenyl, with tetrabutylammonium fluoride(TBAF) in the presence of a suitable solvent, such as for exampletetrahydrofuran. This type of reaction can also be performed in thepresence of a suitable acid, such as for example acetic acid or HCl, anda suitable solvent, such as for example tetrahydrofurane or methanol

(iv) reacting an intermediate of formula

wherein R^(u) is mesylate with

(a) NHR¹⁰R¹¹ optionally in the presence of a suitable base, such as forexample triethylamine, K₂CO₃, Na₂CO₃ or sodium hydride, and optionally asuitable solvent, such as for example acetonitrile, tetrahydrofuran,dioxane, N,N-dimethylformamide or 1-methyl-pyrrolidinone. This type ofreaction can also be performed with a suitable salt of NHR¹⁰R¹¹, e.g.HCl salt of NHR¹⁰R¹¹, or may be performed in the presence of potassiumiodide. In this way compounds wherein R³ represents iodoC₁₋₆alkyl can beobtained; or

(b)

in the presence of a suitable solvent, such as for example acetonitrileor 1-methyl-2-pyrrolidinone optionally in the presence of potassiumiodide or a suitable base, such as for example Na₂CO₃, K₂CO₃ ortriethylamine. This reaction can also be performed with a suitable saltof the suitable nitrogen containing ring within the definition of R⁹ (

represents a suitable nitrogen containing ring (unsubstituted orsubstituted) within the definition of R⁹); or

(c) NHR¹⁰P in the presence of a suitable base, such as for examplesodium hydride, and a suitable solvent, such as for exampledimethylacetamide and wherein P represents a suitable protective group,such as for example C(═O)—O—C(CH₃)₃, followed by a suitable deprotectionreaction;

(v) reacting an intermediate of formula

with W₁—R^(3d) in the presence of a suitable base, such as for examplebutyl lithium, and a suitable solvent, such as for exampletetrahydrofuran, and wherein W₁ represents a suitable leaving group,such as for example halo, e.g. bromo and the like, and R^(3d) representsoptionally substituted C₁₋₆alkyl. This reaction can also be performedwith a protected form of the reactant, namely W₁—R^(3d)—P wherein P is asuitable protective group, such as for example tert-butyldimethylsilylgroup followed by a suitable deprotection reaction, such as in thepresence of a suitable desilylating reagent such as for exampletetrabutylammonium fluoride, in a suitable solvent such as for exampletetrahydrofuran or in the presence of a suitable acid, such as forexample HCl or trifluoroacetic acid, and a suitable solvent, such as forexample an alcohol, e.g. methanol, or dichloromethane;

(vi) reacting an intermediate of formula

with

(a) NHR¹⁰R¹¹ optionally in the presence of a suitable base, such as forexample triethylamine, potassium carbonate, sodium carbonate or sodiumhydride, and optionally a suitable solvent, such as for exampleacetonitrile, tetrahydrofuran, N,N-dimethylformamide; or

(b)

optionally in the presence of a suitable base, such as for exampletriethylamine, potassium carbonate, sodium carbonate or sodium hydride,and optionally a suitable solvent, such as for example acetonitrile,tetrahydrofuran, N,N-dimethylformamide. This reaction can also beperformed with a suitable salt of

which is a suitable nitrogen containing ring (unsubstituted orsubstituted) within the definition of R⁹; or

(c) NHR¹⁰P: in the presence of a suitable base, such as for examplesodium hydride, and a suitable solvent, such as for exampledimethylacetamide and wherein P represents a suitable protective group,such as for example C(═O)—O—C(CH₃)₃, followed by a suitable deprotectionreaction;

(vii) deprotecting an intermediate of formula

in the presence of a suitable acid, such as for example HCl ortrifluoroacetic acid, and a suitable solvent, such as for exampledichloromethane or an alcohol, e.g. methanol;

(viii) reacting an intermediate of formula (XIII) wherein R^(a) isdefined as CO₂Et, said intermediates being represented by formula(XIII-a)

with NHR¹⁴R¹⁵ in the presence of a suitable lewis acid, such as forexample trimethylaluminium, and a suitable solvent, such as for exampletoluene;

(ix) reacting an intermediate of formula

in the presence of a suitable solvent, such as for exampletetrahydrofuran;

(x) deprotecting an intermediate of formula

in the presence of a suitable desilylating reagent such as for exampletetrabutylammonium fluoride, and in the presence of a suitable solvent,such as for example tetrahydrofuran;

(xi) reacting an intermediate of formula

with W₆—R^(3e) wherein R^(3e) represents optionally substitutedC₂₋₆alkynyl and W₆ represents a suitable leaving group such as forexample halo, e.g. chloro, or O—S(═O)₂—CH₃, in the presence of asuitable base, such as for example NaH, and a suitable solvent, such asfor example N,N-dimethylformamide;

(xii) reacting an intermediate of formula

with a suitable acid, such as for example trifluoroacetic acid, in thepresence of a suitable solvent, such as for example tetrahydrofuran.This reaction can also be performed with tetrabutyl ammonium fluoride inthe presence of a suitable solvent such as for example tetrahydrofuran;

(xiii) reacting an intermediate of formula

in the presence of a suitable base, such as for example K₂CO₃, and asuitable solvent, such as for example an alcohol, e.g. methanol and thelike;

(xiv) reacting an intermediate of formula

with di(C₁₋₆alkyl)vinylphosphonate in the presence of a suitablecatalyst, such as for example tri-N-butylphosphine, and a suitablesolvent, such as for example acetonitrile;

(xv) deprotecting an intermediate of formula

wherein the D′N moiety represents a D moiety wherein the D ring moietycontains a nitrogen atom, and P is a suitable protective group, such asfor example —O—C(═O)—C₁₋₆alkyl, in the presence of a suitable base, suchas for example K₂CO₃, and a suitable solvent, such as for example analcohol, e.g. methanol and the like;

(xvi) reacting an intermediate of formula

(XXVI) with W₁₀—CN wherein W₁₀ represents a suitable leaving group, suchas for example halo, e.g. bromo, in the presence of a suitable base,such as for example NaHCO₃, and a suitable solvent, such as for examplewater or dioxane;

(xvii) reacting an intermediate of formula

with a suitable base, such as for example N,N-diisopropylethylamine andtriethylamine, in the presence of a suitable solvent, such as forexample an alcohol, e.g. methanol;

-   -   wherein the variables are as defined herein; and optionally        thereafter converting one compound of the formula (I) into        another compound of the formula (I).

A further embodiment is a process for synthesis of a compound of formula(II) wherein:

an intermediate of formula (VIII) is reacted with

in the presence of a suitable catalyst, such as for examplechloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2′-4′-6′-tri-i-propyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl]palladium(II),a suitable base, such as for example cesium carbonate in a suitablesolvent, such as for example toluene.

Pharmaceutically Acceptable Salts, Solvates or Derivatives Thereof

In this section, as in all other sections of this application, unlessthe context indicates otherwise, references to formula (I) includereferences to all other sub-groups, preferences, embodiments andexamples thereof as defined herein.

Unless otherwise specified, a reference to a particular compound alsoincludes ionic forms, salts, solvates, isomers, tautomers, N-oxides,esters, prodrugs, isotopes and protected forms thereof, for example, asdiscussed below; preferably, the ionic forms, or salts or tautomers orisomers or N-oxides or solvates thereof; and more preferably, the ionicforms, or salts or tautomers or solvates or protected forms thereof,even more preferably the salts or tautomers or solvates thereof. Manycompounds of the formula (I) can exist in the form of salts, for exampleacid addition salts or, in certain cases salts of organic and inorganicbases such as carboxylate, sulphonate and phosphate salts. All suchsalts are within the scope of this invention, and references tocompounds of the formula (I) include the salt forms of the compounds. Itwill be appreciated that references to “derivatives” include referencesto ionic forms, salts, solvates, isomers, tautomers, N-oxides, esters,prodrugs, isotopes and protected forms thereof.

According to one aspect of the invention there is provided a compound asdefined herein or a salt, tautomer, N-oxide or solvate thereof.According to a further aspect of the invention there is provided acompound as defined herein or a salt or solvate thereof. References tocompounds of the formula (I) and sub-groups thereof as defined hereininclude within their scope the salts or solvates or tautomers orN-oxides of the compounds.

The salt forms of the compounds of the invention are typicallypharmaceutically acceptable salts, and examples of pharmaceuticallyacceptable salts are discussed in Berge et al. (1977) “PharmaceuticallyAcceptable Salts,” J. Pharm. Sci., Vol. 66, pp. 1-19. However, saltsthat are not pharmaceutically acceptable may also be prepared asintermediate forms which may then be converted into pharmaceuticallyacceptable salts. Such non-pharmaceutically acceptable salts forms,which may be useful, for example, in the purification or separation ofthe compounds of the invention, also form part of the invention.

The salts of the present invention can be synthesized from the parentcompound that contains a basic or acidic moiety by conventional chemicalmethods such as methods described in Pharmaceutical Salts: Properties,Selection, and Use, P. Heinrich Stahl (Editor), Camille G. Wermuth(Editor), ISBN: 3-90639-026-8, Hardcover, 388 pages, August 2002.Generally, such salts can be prepared by reacting the free acid or baseforms of these compounds with the appropriate base or acid in water orin an organic solvent, or in a mixture of the two; generally, nonaqueousmedia such as ether, ethyl acetate, ethanol, isopropanol, oracetonitrile are used. The compounds of the invention may exist as mono-or di-salts depending upon the pKa of the acid from which the salt isformed.

Acid addition salts may be formed with a wide variety of acids, bothinorganic and organic. Examples of acid addition salts include saltsformed with an acid selected from the group consisting of acetic,2,2-dichloroacetic, adipic, alginic, ascorbic (e.g. L-ascorbic),L-aspartic, benzenesulphonic, benzoic, 4-acetamidobenzoic, butanoic, (+)camphoric, camphor-sulphonic, (+)-(1S)-camphor-10-sulphonic, capric,caproic, caprylic, cinnamic, citric, cyclamic, dodecylsulphuric,ethane-1,2-disulphonic, ethanesulphonic, 2-hydroxyethanesulphonic,formic, fumaric, galactaric, gentisic, glucoheptonic, D-gluconic,glucuronic (e.g. D-glucuronic), glutamic (e.g. L-glutamic),α-oxoglutaric, glycolic, hippuric, hydrobromic, hydrochloric, hydriodic,isethionic, lactic (e.g. (+)-L-lactic, (±)-DL-lactic), lactobionic,maleic, malic, (−)-L-malic, malonic, (±)-DL-mandelic, methanesulphonic,naphthalenesulphonic (e.g. naphthalene-2-sulphonic),naphthalene-1,5-disulphonic, 1-hydroxy-2-naphthoic, nicotinic, nitric,oleic, orotic, oxalic, palmitic, pamoic, phosphoric, propionic,L-pyroglutamic, pyruvic, salicylic, 4-amino-salicylic, sebacic, stearic,succinic, sulphuric, tannic, (+)-L-tartaric, thiocyanic,toluenesulphonic (e.g. p-toluenesulphonic), undecylenic and valericacids, as well as acylated amino acids and cation exchange resins.

One particular group of salts consists of salts formed from acetic,hydrochloric, hydriodic, phosphoric, nitric, sulphuric, citric, lactic,succinic, maleic, malic, isethionic, fumaric, benzenesulphonic,toluenesulphonic, methanesulphonic (mesylate), ethanesulphonic,naphthalenesulphonic, valeric, acetic, propanoic, butanoic, malonic,glucuronic and lactobionic acids. Another group of acid addition saltsincludes salts formed from acetic, adipic, ascorbic, aspartic, citric,DL-Lactic, fumaric, gluconic, glucuronic, hippuric, hydrochloric,glutamic, DL-malic, methanesulphonic, sebacic, stearic, succinic andtartaric acids.

If the compound is anionic, or has a functional group which may beanionic (e.g., —COOH may be —COO), then a salt may be formed with asuitable cation. Examples of suitable inorganic cations include, but arenot limited to, alkali metal ions such as Na⁺ and K⁺, alkaline earthmetal cations such as Ca²⁺ and Mg²⁺, and other cations such as Al³⁺.Examples of suitable organic cations include, but are not limited to,ammonium ion (i.e., NH₄ ⁺) and substituted ammonium ions (e.g., NH₃R⁺,NH₂R₂ ⁺, NHR₃ ⁺, NR₄ ⁺).

Examples of some suitable substituted ammonium ions are those derivedfrom ethylamine, diethylamine, dicyclohexylamine, triethylamine,butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine,benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, aswell as amino acids, such as lysine and arginine. An example of a commonquaternary ammonium ion is N(CH₃)₄ ⁺.

Where the compounds of the formula (I) contain an amine function, thesemay form quaternary ammonium salts, for example by reaction with analkylating agent according to methods well known to the skilled person.Such quaternary ammonium compounds are within the scope of formula (I).Compounds of the formula (I) containing an amine function may also formN-oxides. A reference herein to a compound of the formula (I) thatcontains an amine function also includes the N-oxide. Where a compoundcontains several amine functions, one or more than one nitrogen atom maybe oxidised to form an N-oxide. Particular examples of N-oxides are theN-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containingheterocycle. N-Oxides can be formed by treatment of the correspondingamine with an oxidizing agent such as hydrogen peroxide or a per-acid(e.g. a peroxycarboxylic acid), see for example Advanced OrganicChemistry, by Jerry March, 4th Edition, Wiley Interscience, pages. Moreparticularly, N-oxides can be made by the procedure of L. W. Deady (Syn.Comm. (1977), 7, 509-514) in which the amine compound is reacted withm-chloroperoxybenzoic acid (MCPBA), for example, in an inert solventsuch as dichloromethane.

The compounds of the invention may form solvates, for example with water(i.e., hydrates) or common organic solvents. As used herein, the term“solvate” means a physical association of the compounds of the presentinvention with one or more solvent molecules. This physical associationinvolves varying degrees of ionic and covalent bonding, includinghydrogen bonding. In certain instances the solvate will be capable ofisolation, for example when one or more solvent molecules areincorporated in the crystal lattice of the crystalline solid. The term“solvate” is intended to encompass both solution-phase and isolatablesolvates. Non-limiting examples of suitable solvates include compoundsof the invention in combination with water, isopropanol, ethanol,methanol, DMSO, ethyl acetate, acetic acid or ethanolamine and the like.The compounds of the invention may exert their biological effects whilstthey are in solution.

Solvates are well known in pharmaceutical chemistry. They can beimportant to the processes for the preparation of a substance (e.g. inrelation to their purification, the storage of the substance (e.g. itsstability) and the ease of handling of the substance and are oftenformed as part of the isolation or purification stages of a chemicalsynthesis. A person skilled in the art can determine by means ofstandard and long used techniques whether a hydrate or other solvate hasformed by the isolation conditions or purification conditions used toprepare a given compound. Examples of such techniques includethermogravimetric analysis (TGA), differential scanning calorimetry(DSC), X-ray crystallography (e.g. single crystal X-ray crystallographyor X-ray powder diffraction) and Solid State NMR (SS-NMR, also known asMagic Angle Spinning NMR or MAS-NMR). Such techniques are as much a partof the standard analytical toolkit of the skilled chemist as NMR, IR,HPLC and MS. Alternatively the skilled person can deliberately form asolvate using crystallisation conditions that include an amount of thesolvent required for the particular solvate. Thereafter the standardmethods described above, can be used to establish whether solvates hadformed. Also encompassed by formula (I) are any complexes (e.g.inclusion complexes or clathrates with compounds such as cyclodextrins,or complexes with metals) of the compounds.

Furthermore, the compounds of the present invention may have one or morepolymorph (crystalline) or amorphous forms and as such are intended tobe included in the scope of the invention.

Compounds of the formula (I) may exist in a number of differentgeometric isomeric, and tautomeric forms and references to compounds ofthe formula (I) include all such forms. For the avoidance of doubt,where a compound can exist in one of several geometric isomeric ortautomeric forms and only one is specifically described or shown, allothers are nevertheless embraced by formula (I). Other examples oftautomeric forms include, for example, keto-, enol-, and enolate-forms,as in, for example, the following tautomeric pairs: keto/enol(illustrated below), imine/enamine, amide/imino alcohol,amidine/enediamines, nitroso/oxime, thioketone/enethiol, andnitro/aci-nitro.

Where compounds of the formula (I) contain one or more chiral centres,and can exist in the form of two or more optical isomers, references tocompounds of the formula (I) include all optical isomeric forms thereof(e.g. enantiomers, epimers and diastereoisomers), either as individualoptical isomers, or mixtures (e.g. racemic mixtures) of two or moreoptical isomers, unless the context requires otherwise. The opticalisomers may be characterised and identified by their optical activity(i.e. as + and isomers, or d and l isomers) or they may be characterisedin terms of their absolute stereochemistry using the “R and S”nomenclature developed by Cahn, Ingold and Prelog, see Advanced OrganicChemistry by Jerry March, 4^(th) Edition, John Wiley & Sons, New York,1992, pages 109-114, and see also Cahn, Ingold & Prelog (1966) Angew.Chem. Int. Ed. Engl., 5, 385-415. Optical isomers can be separated by anumber of techniques including chiral chromatography (chromatography ona chiral support) and such techniques are well known to the personskilled in the art. As an alternative to chiral chromatography, opticalisomers can be separated by forming diastereoisomeric salts with chiralacids such as (+)-tartaric acid, (−)-pyroglutamic acid,(−)-di-toluoyl-L-tartaric acid, (+)-mandelic acid, (−)-malic acid, and(−)-camphorsulphonic, separating the diastereoisomers by preferentialcrystallisation, and then dissociating the salts to give the individualenantiomer of the free base.

Where compounds of the formula (I) exist as two or more optical isomericforms, one enantiomer in a pair of enantiomers may exhibit advantagesover the other enantiomer, for example, in terms of biological activity.Thus, in certain circumstances, it may be desirable to use as atherapeutic agent only one of a pair of enantiomers, or only one of aplurality of diastereoisomers. Accordingly, the invention providescompositions containing a compound of the formula (I) having one or morechiral centres, wherein at least 55% (e.g. at least 60%, 65%, 70%, 75%,80%, 85%, 90% or 95%) of the compound of the formula (I) is present as asingle optical isomer (e.g. enantiomer or diastereoisomer). In onegeneral embodiment, 99% or more (e.g. substantially all) of the totalamount of the compound of the formula (I) may be present as a singleoptical isomer (e.g. enantiomer or diastereoisomer). When a specificisomeric form is identified (e.g. S configuration, or E isomer), thismeans that said isomeric form is substantially free of the otherisomer(s), i.e. said isomeric form is present in at least 55%, 60%, 65%,70%, 75%, 80%, 85%, 90%, 95%, 99% or more (e.g. substantially all) ofthe total amount of the compound of the invention.

Hereinbefore or hereinafter, some compounds include the following bond

This indicates that the compound is a single stereoisomer with unknownconfiguration or a mixture of stereoisomers.

The compounds of the invention include compounds with one or moreisotopic substitutions, and a reference to a particular element includeswithin its scope all isotopes of the element. For example, a referenceto hydrogen includes within its scope ¹H, ²H (D), and ³H (T). Similarly,references to carbon and oxygen include within their scope respectively¹²C, ¹³C and ¹⁴C and ¹⁶O and ¹⁸O. The isotopes may be radioactive ornon-radioactive. In one embodiment of the invention, the compoundscontain no radioactive isotopes. Such compounds are preferred fortherapeutic use. In another embodiment, however, the compound maycontain one or more radioisotopes. Compounds containing suchradioisotopes may be useful in a diagnostic context.

Esters such as carboxylic acid esters and acyloxy esters of thecompounds of formula (I) bearing a carboxylic acid group or a hydroxylgroup are also embraced by formula (I). In one embodiment of theinvention, formula (I) includes within its scope esters of compounds ofthe formula (I) bearing a carboxylic acid group or a hydroxyl group. Inanother embodiment of the invention, formula (I) does not include withinits scope esters of compounds of the formula (I) bearing a carboxylicacid group or a hydroxyl group. Examples of esters are compoundscontaining the group —C(═O)OR, wherein R is an ester substituent, forexample, a C₁₋₆ alkyl group, a heterocyclyl group, or a C₅₋₂₀ arylgroup, preferably a C₁₋₆ alkyl group. Particular examples of estergroups include, but are not limited to, —C(═O)OCH₃, —C(═O)OCH₂CH₃,—C(═O)OC(CH₃)₃, and —C(═O)OPh. Examples of acyloxy (reverse ester)groups are represented by —OC(═O)R, wherein R is an acyloxy substituent,for example, a C₁₋₇ alkyl group, a C₃₋₂₀ heterocyclyl group, or a C₅₋₂₀aryl group, preferably a C₁₋₇ alkyl group. Particular examples ofacyloxy groups include, but are not limited to, —OC(═O)CH₃ (acetoxy),—OC(═O)CH₂CH₃, —OC(═O)C(CH₃)₃, —OC(═O)Ph, and —OC(═O)CH₂Ph.

For example, some prodrugs are esters of the active compound (e.g., aphysiologically acceptable metabolically labile ester). By “prodrugs” ismeant for example any compound that is converted in vivo into abiologically active compound of the formula (I). During metabolism, theester group (—C(═O)OR) is cleaved to yield the active drug. Such estersmay be formed by esterification, for example, of any of the carboxylicacid groups (—C(═O)OH) in the parent compound, with, where appropriate,prior protection of any other reactive groups present in the parentcompound, followed by deprotection if required.

Examples of such metabolically labile esters include those of theformula —C(═O)OR wherein R is: C₁₋₆alkyl (e.g., -Me, -Et, -nPr, -iPr,-nBu, -sBu, -iBu, -tBu); C₁₋₆aminoalkyl [e.g., aminoethyl;2-(N,N-diethylamino)ethyl; 2-(4-morpholino)ethyl); and acyloxy-C₁₋₇alkyl[e.g., acyloxymethyl; acyloxyethyl; pivaloyloxymethyl; acetoxymethyl;1-acetoxyethyl; 1-(1-methoxy-1-methyl)ethyl-carbonyloxyethyl;1-(benzoyloxy)ethyl; isopropoxy-carbonyloxymethyl;1-isopropoxy-carbonyloxyethyl; cyclohexyl-carbonyloxymethyl;1-cyclohexyl-carbonyloxyethyl; cyclohexyloxy-carbonyloxymethyl;1-cyclohexyloxy-carbonyloxyethyl; (4-tetrahydropyranyloxy)carbonyloxymethyl; 1-(4-tetrahydropyranyloxy)carbonyloxyethyl;(4-tetrahydropyranyl)carbonyloxymethyl; and1-(4-tetrahydropyranyl)carbonyloxyethyl]. Also, some prodrugs areactivated enzymatically to yield the active compound, or a compoundwhich, upon further chemical reaction, yields the active compound (forexample, as in antigen-directed enzyme pro-drug therapy (ADEPT),gene-directed enzyme pro-drug therapy (GDEPT) and ligand-directed enzymepro-drug therapy (LIDEPT) etc.). For example, the prodrug may be a sugarderivative or other glycoside conjugate, or may be an amino acid esterderivative.

Protein Tyrosine Kinases (PTK)

The compounds of the invention described herein inhibit or modulate theactivity of certain tyrosine kinases, and thus the compounds will beuseful in the treatment or prophylaxis, in particular the treatment, ofdisease states or conditions mediated by those tyrosine kinases, inparticular FGFR.

FGFR

The fibroblast growth factor (FGF) family of protein tyrosine kinase(PTK) receptors regulates a diverse array of physiologic functionsincluding mitogenesis, wound healing, cell differentiation andangiogenesis, and development. Both normal and malignant cell growth aswell as proliferation are affected by changes in local concentration ofFGFs, extracellular signalling molecules which act as autocrine as wellas paracrine factors. Autocrine FGF signalling may be particularlyimportant in the progression of steroid hormone-dependent cancers to ahormone independent state. FGFs and their receptors are expressed atincreased levels in several tissues and cell lines and overexpression isbelieved to contribute to the malignant phenotype. Furthermore, a numberof oncogenes are homologues of genes encoding growth factor receptors,and there is a potential for aberrant activation of FGF-dependentsignalling in human pancreatic cancer (Knights et al., Pharmacology andTherapeutics 2010 125:1 (105-117); Korc M. et al Current Cancer DrugTargets 2009 9:5 (639-651)).

The two prototypic members are acidic fibroblast growth factor (aFGF orFGF1) and basic fibroblast growth factor (bFGF or FGF2), and to date, atleast twenty distinct FGF family members have been identified. Thecellular response to FGFs is transmitted via four types of high affinitytransmembrane protein tyrosine-kinase fibroblast growth factor receptors(FGFR) numbered 1 to 4 (FGFR1 to FGFR4).

Disruption of the FGFR1 pathway should affect tumor cell proliferationsince this kinase is activated in many tumor types in addition toproliferating endothelial cells. The over-expression and activation ofFGFR1 in tumor-associated vasculature has suggested a role for thesemolecules in tumor angiogenesis.

A recent study has shown a link between FGFR1 expression andtumorigenicity in Classic Lobular Carcinomas (CLC). CLCs account for10-15% of all breast cancers and, in general, lack p53 and Her2expression whilst retaining expression of the oestrogen receptor. A geneamplification of 8p12-p11.2 was demonstrated in ˜50% of CLC cases andthis was shown to be linked with an increased expression of FGFR1.Preliminary studies with siRNA directed against FGFR1, or a smallmolecule inhibitor of the receptor, showed cell lines harbouring thisamplification to be particularly sensitive to inhibition of thissignalling pathway. Rhabdomyosarcoma (RMS) is the most common pediatricsoft tissue sarcoma likely results from abnormal proliferation anddifferentiation during skeletal myogenesis. FGFR1 is over-expressed inprimary rhabdomyosarcoma tumors and is associated with hypomethylationof a 5′ CpG island and abnormal expression of the AKT1, NOG, and BMP4genes. FGFR1 has also been linked to squamous lung cancer, colorectalcancer, glioblastoma, astrocytomas, prostate cancer, small cell lungcancer, melanoma, head and neck cancer, thyroid cancer, uterine cancer.

Fibroblast growth factor receptor 2 has high affinity for the acidicand/or basic fibroblast growth factors, as well as the keratinocytegrowth factor ligands. Fibroblast growth factor receptor 2 alsopropagates the potent osteogenic effects of FGFs during osteoblastgrowth and differentiation. Mutations in fibroblast growth factorreceptor 2, leading to complex functional alterations, were shown toinduce abnormal ossification of cranial sutures (craniosynostosis),implying a major role of FGFR signalling in intramembranous boneformation. For example, in Apert (AP) syndrome, characterized bypremature cranial suture ossification, most cases are associated withpoint mutations engendering gain-of-function in fibroblast growth factorreceptor 2. In addition, mutation screening in patients with syndromiccraniosynostoses indicates that a number of recurrent FGFR2 mutationsaccounts for severe forms of Pfeiffer syndrome. Particular mutations ofFGFR2 include W290C, D321A, Y340C, C342R, C342S, C342W, N549H, K641R inFGFR2.

Several severe abnormalities in human skeletal development, includingApert, Crouzon, Jackson-Weiss, Beare-Stevenson cutis gyrata, andPfeiffer syndromes are associated with the occurrence of mutations infibroblast growth factor receptor 2. Most, if not all, cases of PfeifferSyndrome (PS) are also caused by de novo mutation of the fibroblastgrowth factor receptor 2 gene, and it was recently shown that mutationsin fibroblast growth factor receptor 2 break one of the cardinal rulesgoverning ligand specificity. Namely, two mutant splice forms offibroblast growth factor receptor, FGFR2c and FGFR2b, have acquired theability to bind to and be activated by atypical FGF ligands. This lossof ligand specificity leads to aberrant signalling and suggests that thesevere phenotypes of these disease syndromes result from ectopicligand-dependent activation of fibroblast growth factor receptor 2.

Genetic aberrations of the FGFR3 receptor tyrosine kinase such aschromosomal translocations or point mutations result in ectopicallyexpressed or deregulated, constitutively active, FGFR3 receptors. Suchabnormalities are linked to a subset of multiple myelomas and inbladder, hepatocellular, oral squamous cell carcinoma and cervicalcarcinomas. Accordingly, FGFR3 inhibitors would be useful in thetreatment of multiple myeloma, bladder and cervical carcinomas. FGFR3 isalso over-expressed in bladder cancer, in particular invasive bladdercancer. FGFR3 is frequently activated by mutation in urothelialcarcinoma (UC). Increased expression was associated with mutation (85%of mutant tumors showed high-level expression) but also 42% of tumorswith no detectable mutation showed over-expression, including manymuscle-invasive tumors. FGFR3 is also linked to endometrial and thyroidcancer.

Over expression of FGFR4 has been linked to poor prognosis in bothprostate and thyroid carcinomas. In addition a germline polymorphism(Gly388Arg) is associated with increased incidence of lung, breast,colon, liver (HCC) and prostate cancers. In addition, a truncated formof FGFR4 (including the kinase domain) has also been found to be presentin 40% of pituitary tumours but not present in normal tissue. FGFR4overexpression has been observed in liver, colon and lung tumours. FGFR4has been implicated in colorectal and liver cancer where expression ofits ligand FGF19 is frequently elevated. FGFR4 is also linked toastrocytomas, rhabdomyosarcoma.

Fibrotic conditions are a major medical problem resulting from abnormalor excessive deposition of fibrous tissue. This occurs in many diseases,including liver cirrhosis, glomerulonephritis, pulmonary fibrosis,systemic fibrosis, rheumatoid arthritis, as well as the natural processof wound healing. The mechanisms of pathological fibrosis are not fullyunderstood but are thought to result from the actions of variouscytokines (including tumor necrosis factor (TNF), fibroblast growthfactors (FGF's), platelet derived growth factor (PDGF) and transforminggrowth factor beta. (TGFβ) involved in the proliferation of fibroblastsand the deposition of extracellular matrix proteins (including collagenand fibronectin). This results in alteration of tissue structure andfunction and subsequent pathology.

A number of preclinical studies have demonstrated the up-regulation offibroblast growth factors in preclinical models of lung fibrosis. TGFβ1and PDGF have been reported to be involved in the fibrogenic process andfurther published work suggests the elevation of FGF's and consequentincrease in fibroblast proliferation, may be in response to elevatedTGFβ1. The potential therapeutic benefit of targeting the fibroticmechanism in conditions such as idiopathic pulmonary fibrosis (IPF) issuggested by the reported clinical effect of the anti-fibrotic agentpirfenidone. Idiopathic pulmonary fibrosis (also referred to asCryptogenic fibrosing alveolitis) is a progressive condition involvingscarring of the lung. Gradually, the air sacs of the lungs becomereplaced by fibrotic tissue, which becomes thicker, causing anirreversible loss of the tissue's ability to transfer oxygen into thebloodstream. The symptoms of the condition include shortness of breath,chronic dry coughing, fatigue, chest pain and loss of appetite resultingin rapid weight loss. The condition is extremely serious withapproximately 50% mortality after 5 years.

As such, the compounds which inhibit FGFR will be useful in providing ameans of preventing the growth or inducing apoptosis in tumours,particularly by inhibiting angiogenesis. It is therefore anticipatedthat the compounds will prove useful in treating or preventingproliferative disorders such as cancers. In particular tumours withactivating mutants of receptor tyrosine kinases or upregulation ofreceptor tyrosine kinases may be particularly sensitive to theinhibitors. Patients with activating mutants of any of the isoforms ofthe specific RTKs discussed herein may also find treatment with RTKinhibitors particularly beneficial.

Vascular Endothelial Growth Factor (VEGFR)

Chronic proliferative diseases are often accompanied by profoundangiogenesis, which can contribute to or maintain an inflammatory and/orproliferative state, or which leads to tissue destruction through theinvasive proliferation of blood vessels.

Angiogenesis is generally used to describe the development of new orreplacement blood vessels, or neovascularisation. It is a necessary andphysiological normal process by which vasculature is established in theembryo. Angiogenesis does not occur, in general, in most normal adulttissues, exceptions being sites of ovulation, menses and wound healing.Many diseases, however, are characterized by persistent and unregulatedangiogenesis. For instance, in arthritis, new capillary blood vesselsinvade the joint and destroy cartilage. In diabetes (and in manydifferent eye diseases), new vessels invade the macula or retina orother ocular structures, and may cause blindness. The process ofatherosclerosis has been linked to angiogenesis. Tumor growth andmetastasis have been found to be angiogenesis-dependent.

The recognition of the involvement of angiogenesis in major diseases hasbeen accompanied by research to identify and develop inhibitors ofangiogenesis. These inhibitors are generally classified in response todiscrete targets in the angiogenesis cascade, such as activation ofendothelial cells by an angiogenic signal; synthesis and release ofdegradative enzymes; endothelial cell migration; proliferation ofendothelial cells; and formation of capillary tubules. Therefore,angiogenesis occurs in many stages and attempts are underway to discoverand develop compounds that work to block angiogenesis at these variousstages.

There are publications that teach that inhibitors of angiogenesis,working by diverse mechanisms, are beneficial in diseases such as cancerand metastasis, ocular diseases, arthritis and hemangioma.

Vascular endothelial growth factor (VEGF), a polypeptide, is mitogenicfor endothelial cells in vitro and stimulates angiogenic responses invivo. VEGF has also been linked to inappropriate angiogenesis. VEGFR(s)are protein tyrosine kinases (PTKs). PTKs catalyze the phosphorylationof specific tyrosine residues in proteins involved in cell function thusregulating cell growth, survival and differentiation.

Three PTK receptors for VEGF have been identified: VEGFR-1 (Flt-1);VEGFR-2 (Flk-1 or KDR) and VEGFR-3 (Flt-4). These receptors are involvedin angiogenesis and participate in signal transduction. Of particularinterest is VEGFR-2, which is a transmembrane receptor PTK expressedprimarily in endothelial cells. Activation of VEGFR-2 by VEGF is acritical step in the signal transduction pathway that initiates tumourangiogenesis. VEGF expression may be constitutive to tumour cells andcan also be upregulated in response to certain stimuli. One such stimuliis hypoxia, where VEGF expression is upregulated in both tumour andassociated host tissues. The VEGF ligand activates VEGFR-2 by bindingwith its extracellular VEGF binding site. This leads to receptordimerization of VEGFRs and autophosphorylation of tyrosine residues atthe intracellular kinase domain of VEGFR-2. The kinase domain operatesto transfer a phosphate from ATP to the tyrosine residues, thusproviding binding sites for signalling proteins downstream of VEGFR-2leading ultimately to initiation of angiogenesis.

Inhibition at the kinase domain binding site of VEGFR-2 would blockphosphorylation of tyrosine residues and serve to disrupt initiation ofangiogenesis.

Angiogenesis is a physiologic process of new blood vessel formationmediated by various cytokines called angiogenic factors. Although itspotential pathophysiologic role in solid tumors has been extensivelystudied for more than 3 decades, enhancement of angiogenesis in chroniclymphocytic leukemia (CLL) and other malignant hematological disordershas been recognized more recently. An increased level of angiogenesishas been documented by various experimental methods both in bone marrowand lymph nodes of patients with CLL. Although the role of angiogenesisin the pathophysiology of this disease remains to be fully elucidated,experimental data suggest that several angiogenic factors play a role inthe disease progression. Biologic markers of angiogenesis were alsoshown to be of prognostic relevance in CLL. This indicates that VEGFRinhibitors may also be of benefit for patients with leukemia's such asCLL.

In order for a tumour mass to get beyond a critical size, it mustdevelop an associated vasculature. It has been proposed that targeting atumor vasculature would limit tumor expansion and could be a usefulcancer therapy. Observations of tumor growth have indicated that smalltumour masses can persist in a tissue without any tumour-specificvasculature. The growth arrest of nonvascularized tumors has beenattributed to the effects of hypoxia at the center of the tumor. Morerecently, a variety of proangiogenic and antiangiogenic factors havebeen identified and have led to the concept of the “angiogenic switch,”a process in which disruption of the normal ratio of angiogenic stimuliand inhibitors in a tumor mass allows for autonomous vascularization.The angiogenic switch appears to be governed by the same geneticalterations that drive malignant conversion: the activation of oncogenesand the loss of tumour suppressor genes. Several growth factors act aspositive regulators of angiogenesis. Foremost among these are vascularendothelial growth factor (VEGF), basic fibroblast growth factor (bFGF),and angiogenin. Proteins such as thrombospondin (Tsp-1), angiostatin,and endostatin function as negative regulators of angiogenesis.

Inhibition of VEGFR2 but not VEGFR1 markedly disrupts angiogenicswitching, persistent angiogenesis, and initial tumor growth in a mousemodel. In late-stage tumors, phenotypic resistance to VEGFR2 blockadeemerged, as tumors regrew during treatment after an initial period ofgrowth suppression. This resistance to VEGF blockade involvesreactivation of tumour angiogenesis, independent of VEGF and associatedwith hypoxia-mediated induction of other proangiogenic factors,including members of the FGF family. These other proangiogenic signalsare functionally implicated in the revascularization and regrowth oftumours in the evasion phase, as FGF blockade impairs progression in theface of VEGF inhibition.

There is evidence for normalization of glioblastoma blood vessels inpatients treated with a pan-VEGF receptor tyrosine kinase inhibitor,AZD2171, in a phase 2 study. MRI determination of vessel normalizationin combination with circulating biomarkers provides for an effectivemeans to assess response to antiangiogenic agents.

PDGFR

A malignant tumour is the product of uncontrolled cell proliferation.Cell growth is controlled by a delicate balance between growth-promotingand growth-inhibiting factors. In normal tissue the production andactivity of these factors results in differentiated cells growing in acontrolled and regulated manner that maintains the normal integrity andfunctioning of the organ. The malignant cell has evaded this control;the natural balance is disturbed (via a variety of mechanisms) andunregulated, aberrant cell growth occurs. A growth factor of importancein tumour development is the platelet-derived growth factor (PDGF) thatcomprises a family of peptide growth factors that signal through cellsurface tyrosine kinase receptors (PDGFR) and stimulate various cellularfunctions including growth, proliferation, and differentiation.

Advantages of a Selective Inhibitor

Development of FGFR kinase inhibitors with a differentiated selectivityprofile provides a new opportunity to use these targeted agents inpatient sub-groups whose disease is driven by FGFR deregulation.Compounds that exhibit reduced inhibitory action on additional kinases,particularly VEGFR2 and PDGFR-beta, offer the opportunity to have adifferentiated side-effect or toxicity profile and as such allow for amore effective treatment of these indications. Inhibitors of VEGFR2 andPDGFR-beta are associated with toxicities such as hypertension or oedemarespectively. In the case of VEGFR2 inhibitors this hypertensive effectis often dose limiting, may be contraindicated in certain patientpopulations and requires clinical management.

Biological Activity and Therapeutic Uses

The compounds of the invention, and subgroups thereof, have fibroblastgrowth factor receptor (FGFR) inhibiting or modulating activity and/orvascular endothelial growth factor receptor (VEGFR) inhibiting ormodulating activity, and/or platelet derived growth factor receptor(PDGFR) inhibiting or modulating activity, and which will be useful inpreventing or treating disease states or conditions described herein. Inaddition the compounds of the invention, and subgroups thereof, will beuseful in preventing or treating diseases or condition mediated by thekinases. References to the preventing or prophylaxis or treatment of adisease state or condition such as cancer include within their scopealleviating or reducing the incidence of cancer.

As used herein, the term “modulation”, as applied to the activity of akinase, is intended to define a change in the level of biologicalactivity of the protein kinase. Thus, modulation encompassesphysiological changes which effect an increase or decrease in therelevant protein kinase activity. In the latter case, the modulation maybe described as “inhibition”. The modulation may arise directly orindirectly, and may be mediated by any mechanism and at anyphysiological level, including for example at the level of geneexpression (including for example transcription, translation and/orpost-translational modification), at the level of expression of genesencoding regulatory elements which act directly or indirectly on thelevels of kinase activity. Thus, modulation may implyelevated/suppressed expression or over- or under-expression of a kinase,including gene amplification (i.e. multiple gene copies) and/orincreased or decreased expression by a transcriptional effect, as wellas hyper- (or hypo-)activity and (de)activation of the protein kinase(s)(including (de)activation) by mutation(s). The terms “modulated”,“modulating” and “modulate” are to be interpreted accordingly.

As used herein, the term “mediated”, as used e.g. in conjunction with akinase as described herein (and applied for example to variousphysiological processes, diseases, states, conditions, therapies,treatments or interventions) is intended to operate limitatively so thatthe various processes, diseases, states, conditions, treatments andinterventions to which the term is applied are those in which the kinaseplays a biological role. In cases where the term is applied to adisease, state or condition, the biological role played by a kinase maybe direct or indirect and may be necessary and/or sufficient for themanifestation of the symptoms of the disease, state or condition (or itsaetiology or progression). Thus, kinase activity (and in particularaberrant levels of kinase activity, e.g. kinase over-expression) neednot necessarily be the proximal cause of the disease, state orcondition: rather, it is contemplated that the kinase mediated diseases,states or conditions include those having multifactorial aetiologies andcomplex progressions in which the kinase in question is only partiallyinvolved. In cases where the term is applied to treatment, prophylaxisor intervention, the role played by the kinase may be direct or indirectand may be necessary and/or sufficient for the operation of thetreatment, prophylaxis or outcome of the intervention. Thus, a diseasestate or condition mediated by a kinase includes the development ofresistance to any particular cancer drug or treatment.

Thus, for example, the compounds of the invention may be useful inalleviating or reducing the incidence of cancer.

More particularly, the compounds of the formulae (I) and sub-groupsthereof are inhibitors of FGFRs. For example, compounds of the inventionhave activity against FGFR1, FGFR2, FGFR3, and/or FGFR4, and inparticular FGFRs selected from FGFR1, FGFR2 and FGFR3; or in particularthe compounds of formula (I) and sub-groups thereof are inhibitors ofFGFR4.

Preferred compounds are compounds that inhibit one or more FGFR selectedfrom FGFR1, FGFR2, FGFR3, and FGFR4. Preferred compounds of theinvention are those having IC₅₀ values of less than 0.1 μM.

Compounds of the invention also have activity against VEGFR.

In addition many of the compounds of the invention exhibit selectivityfor the FGFR 1, 2, and/or 3, and/or 4 compared to VEGFR (in particularVEGFR2) and/or PDGFR and such compounds represent one preferredembodiment of the invention. In particular, the compounds exhibitselectivity over VEGFR2. For example, many compounds of the inventionhave IC₅₀ values against FGFR1, 2 and/or 3 and/or 4 that are between atenth and a hundredth of the IC₅₀ against VEGFR (in particular VEGFR2)and/or PDGFR B. In particular preferred compounds of the invention haveat least 10 times greater activity against or inhibition of FGFR inparticular FGFR1, FGFR2, FGFR3 and/or FGFR4 than VEGFR2. More preferablythe compounds of the invention have at least 100 times greater activityagainst or inhibition of FGFR in particular FGFR1, FGFR2, FGFR3 and/orFGFR4 than VEGFR2. This can be determined using the methods describedherein.

As a consequence of their activity in modulating or inhibiting FGFR,and/or VEGFR kinases, the compounds will be useful in providing a meansof preventing the growth or inducing apoptosis of neoplasias,particularly by inhibiting angiogenesis. It is therefore anticipatedthat the compounds will prove useful in treating or preventingproliferative disorders such as cancers. In addition, the compounds ofthe invention could be useful in the treatment of diseases in whichthere is a disorder of proliferation, apoptosis or differentiation.

In particular tumours with activating mutants of VEGFR or upregulationof VEGFR and patients with elevated levels of serum lactatedehydrogenase may be particularly sensitive to the compounds of theinvention. Patients with activating mutants of any of the isoforms ofthe specific RTKs discussed herein may also find treatment with thecompounds of the invention particularly beneficial. For example, VEGFRoverexpression in acute leukemia cells where the clonal progenitor mayexpress VEGFR. Also, particular tumours with activating mutants orupregulation or overexpression of any of the isoforms of FGFR such asFGFR1, FGFR2 or FGFR3 or FGFR4 may be particularly sensitive to thecompounds of the invention and thus patients as discussed herein withsuch particular tumours may also find treatment with the compounds ofthe invention particularly beneficial. It may be preferred that thetreatment is related to or directed at a mutated form of one of thereceptor tyrosine kinases, such as discussed herein. Diagnosis oftumours with such mutations could be performed using techniques known toa person skilled in the art and as described herein such as RTPCR andFISH.

Examples of cancers which may be treated (or inhibited) include, but arenot limited to, a carcinoma, for example a carcinoma of the bladder,breast, colon (e.g. colorectal carcinomas such as colon adenocarcinomaand colon adenoma), kidney, urothelial, uterus, epidermis, liver, lung(for example adenocarcinoma, small cell lung cancer and non-small celllung carcinomas, squamous lung cancer), oesophagus, head and neck, gallbladder, ovary, pancreas (e.g. exocrine pancreatic carcinoma), stomach,gastrointestinal (also known as gastric) cancer (e.g. gastrointestinalstromal tumours), cervix, endometrium, thyroid, prostate, or skin (forexample squamous cell carcinoma or dermatofibrosarcoma protuberans);pituitary cancer, a hematopoietic tumour of lymphoid lineage, forexample leukemia, acute lymphocytic leukemia, chronic lymphocyticleukemia, B-cell lymphoma (e.g. diffuse large B-cell lymphoma), T-celllymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy celllymphoma, or Burkett's lymphoma; a hematopoietic tumour of myeloidlineage, for example leukemias, acute and chronic myelogenous leukemias,chronic myelomonocytic leukemia (CMML), myeloproliferative disorder,myeloproliferative syndrome, myelodysplastic syndrome, or promyelocyticleukemia; multiple myeloma; thyroid follicular cancer; hepatocellularcancer, a tumour of mesenchymal origin (e.g. Ewing's sarcoma), forexample fibrosarcoma or rhabdomyosarcoma; a tumour of the central orperipheral nervous system, for example astrocytoma, neuroblastoma,glioma (such as glioblastoma multiforme) or schwannoma; melanoma;seminoma; teratocarcinoma; osteosarcoma; xeroderma pigmentosum;keratoctanthoma; thyroid follicular cancer; or Kaposi's sarcoma. Inparticular, squamous lung cancer, breast cancer, colorectal cancer,glioblastoma, astrocytomas, prostate cancer, small cell lung cancer,melanoma, head and neck cancer, thyroid cancer, uterine cancer, gastriccancer, hepatocellular cancer, cervix cancer, multiple myeloma, bladdercancer, endometrial cancer, urothelial cancer, colon cancer,rhabdomyosarcoma, pituitary gland cancer.

Certain cancers are resistant to treatment with particular drugs. Thiscan be due to the type of the tumour or can arise due to treatment withthe compound. In this regard, references to multiple myeloma includesbortezomib sensitive multiple myeloma or refractory multiple myeloma.Similarly, references to chronic myelogenous leukemia includes imitanibsensitive chronic myelogenous leukemia and refractory chronicmyelogenous leukemia. Chronic myelogenous leukemia is also known aschronic myeloid leukemia, chronic granulocytic leukemia or CML.Likewise, acute myelogenous leukemia, is also called acute myeloblasticleukemia, acute granulocytic leukemia, acute nonlymphocytic leukaemia orAML.

The compounds of the invention can also be used in the treatment ofhematopoetic diseases of abnormal cell proliferation whetherpre-malignant or stable such as myeloproliferative diseases.Myeloproliferative diseases (“MPD”s) are a group of diseases of the bonemarrow in which excess cells are produced. They are related to, and mayevolve into, myelodysplastic syndrome. Myeloproliferative diseasesinclude polycythemia vera, essential thrombocythemia and primarymyelofibrosis. A further haematological disorder is hypereosinophilicsyndrome. T-cell lymphoproliferative diseases include those derived fromnatural Killer cells.

In addition the compounds of the invention can be used togastrointestinal (also known as gastric) cancer e.g. gastrointestinalstromal tumours. Gastrointestinal cancer refers to malignant conditionsof the gastrointestinal tract, including the esophagus, stomach, liver,biliary system, pancreas, bowels, and anus.

Thus, in the pharmaceutical compositions, uses or methods of thisinvention for treating a disease or condition comprising abnormal cellgrowth, the disease or condition comprising abnormal cell growth in oneembodiment is a cancer.

Particular subsets of cancers include multiple myeloma, bladder,cervical, prostate and thyroid carcinomas, lung, breast, and coloncancers.

A further subset of cancers includes multiple myeloma, bladder,hepatocellular, oral squamous cell carcinoma and cervical carcinomas.

The compound of the invention, having FGFR such as FGFR1 inhibitoryactivity, may be particularly useful in the treatment or prevention ofbreast cancer in particular Classic Lobular Carcinomas (CLC).

As the compounds of the invention have FGFR4 activity they will also beuseful in the treatment of prostate or pituitary cancers, or they willbe useful in the treatment of breast cancer, lung cancer, prostatecancer, liver cancer (HCC) or lung cancer.

In particular the compounds of the invention as FGFR inhibitors, areuseful in the treatment of multiple myeloma, myeloproliferativedisorders, endometrial cancer, prostate cancer, bladder cancer, lungcancer, ovarian cancer, breast cancer, gastric cancer, colorectalcancer, and oral squamous cell carcinoma.

Further subsets of cancer are multiple myeloma, endometrial cancer,bladder cancer, cervical cancer, prostate cancer, lung cancer, breastcancer, colorectal cancer and thyroid carcinomas.

In particular the compounds of the invention are useful in the treatmentof multiple myeloma (in particular multiple myeloma with t(4;14)translocation or overexpressing FGFR3), prostate cancer (hormonerefractory prostrate carcinomas), endometrial cancer (in particularendometrial tumours with activating mutations in FGFR2) and breastcancer (in particular lobular breast cancer).

In particular, the compounds of the invention have activity againsttumours with FGFR3-TACC3 translocation, in particular bladder or braintumours with FGFR3-TACC3 translocation.

In particular the compounds are useful in the treatment of lobularcarcinomas such as CLC (Classic lobular carcinoma).

As the compounds have activity against FGFR3 they will be useful in thetreatment of multiple myeloma and bladder cancer.

In particular the compounds are useful for the treatment of t(4;14)translocation positive multiple myeloma.

In one embodiment the compounds may be useful for the treatment ofsarcoma. In one embodiment the compounds may be useful for the treatmentof lung cancer, e.g. squamous cell carcinoma.

As the compounds have activity against FGFR2 they will be useful in thetreatment of endometrial, ovarian, gastric, hepatocellular, uterine,cervix and colorectal cancers. FGFR2 is also overexpressed in epithelialovarian cancer, therefore the compounds of the invention may bespecifically useful in treating ovarian cancer such as epithelialovarian cancer.

In one embodiment, the compounds may be useful for the treatment of lungcancer, in particular NSCLC, squamous cell carcinoma, liver cancer,kidney cancer, breast cancer, colon cancer, colorectal cancer, prostatecancer.

Compounds of the invention may also be useful in the treatment oftumours pre-treated with VEGFR2 inhibitor or VEGFR2 antibody (e.g.Avastin).

In particular the compounds of the invention may be useful in thetreatment of VEGFR2-resistant tumours. VEGFR2 inhibitors and antibodiesare used in the treatment of thyroid and renal cell carcinomas,therefore the compounds of the invention may be useful in the treatmentof VEGFR2-resistant thyroid and renal cell carcinomas.

The cancers may be cancers which are sensitive to inhibition of any oneor more FGFRs selected from FGFR1, FGFR2, FGFR3, FGFR4, for example, oneor more FGFRs selected from FGFR1, FGFR2 or FGFR3.

Whether or not a particular cancer is one which is sensitive toinhibition of FGFR or VEGFR signalling may be determined by means of acell growth assay as set out below or by a method as set out in thesection headed “Methods of Diagnosis”.

The compounds of the invention, and in particular those compounds havingFGFR, or VEGFR inhibitory activity, may be particularly useful in thetreatment or prevention of cancers of a type associated with orcharacterised by the presence of elevated levels of FGFR, or VEGFR, forexample the cancers referred to in this context in the introductorysection of this application.

The compounds of the present invention may be useful for the treatmentof the adult population. The compounds of the present invention may beuseful for the treatment of the pediatric population.

It has been discovered that some FGFR inhibitors can be used incombination with other anticancer agents. For example, it may bebeneficial to combine an inhibitor that induces apoptosis with anotheragent which acts via a different mechanism to regulate cell growth thustreating two of the characteristic features of cancer development.Examples of such combinations are set out below.

The compounds of the invention may be useful in treating otherconditions which result from disorders in proliferation such as type IIor non-insulin dependent diabetes mellitus, autoimmune diseases, headtrauma, stroke, epilepsy, neurodegenerative diseases such asAlzheimer's, motor neurone disease, progressive supranuclear palsy,corticobasal degeneration and Pick's disease for example autoimmunediseases and neurodegenerative diseases.

One sub-group of disease states and conditions that the compounds of theinvention may be useful consists of inflammatory diseases,cardiovascular diseases and wound healing.

FGFR, and VEGFR are also known to play a role in apoptosis,angiogenesis, proliferation, differentiation and transcription andtherefore the compounds of the invention could also be useful in thetreatment of the following diseases other than cancer; chronicinflammatory diseases, for example systemic lupus erythematosus,autoimmune mediated glomerulonephritis, rheumatoid arthritis, psoriasis,inflammatory bowel disease, autoimmune diabetes mellitus, Eczemahypersensitivity reactions, asthma, COPD, rhinitis, and upperrespiratory tract disease; cardiovascular diseases for example cardiachypertrophy, restenosis, atherosclerosis; neurodegenerative disorders,for example Alzheimer's disease, AIDS-related dementia, Parkinson'sdisease, amyotropic lateral sclerosis, retinitis pigmentosa, spinalmuscular atropy and cerebellar degeneration; glomerulonephritis;myelodysplastic syndromes, ischemic injury associated myocardialinfarctions, stroke and reperfusion injury, arrhythmia, atherosclerosis,toxin-induced or alcohol related liver diseases, haematologicaldiseases, for example, chronic anemia and aplastic anemia; degenerativediseases of the musculoskeletal system, for example, osteoporosis andarthritis, aspirin-sensitive rhinosinusitis, cystic fibrosis, multiplesclerosis, kidney diseases and cancer pain.

In addition, mutations of FGFR2 are associated with several severeabnormalities in human skeletal development and thus the compounds ofinvention could be useful in the treatment of abnormalities in humanskeletal development, including abnormal ossification of cranial sutures(craniosynostosis), Apert (AP) syndrome, Crouzon syndrome, Jackson-Weisssyndrome, Beare-Stevenson cutis gyrate syndrome, and Pfeiffer syndrome.

The compound of the invention, having FGFR such as FGFR2 or FGFR3inhibitory activity, may be particularly useful in the treatment orprevention of the skeletal diseases. Particular skeletal diseases areachondroplasia or thanatophoric dwarfism (also known as thanatophoricdysplasia).

The compound of the invention, having FGFR such as FGFR1, FGFR2 or FGFR3inhibitory activity, may be particularly useful in the treatment orprevention in pathologies in which progressive fibrosis is a symptom.Fibrotic conditions in which the compounds of the inventions may beuseful in the treatment of include diseases exhibiting abnormal orexcessive deposition of fibrous tissue for example in liver cirrhosis,glomerulonephritis, pulmonary fibrosis, systemic fibrosis, rheumatoidarthritis, as well as the natural process of wound healing. Inparticular the compounds of the inventions may also be useful in thetreatment of lung fibrosis in particular in idiopathic pulmonaryfibrosis.

The over-expression and activation of FGFR and VEGFR in tumor-associatedvasculature has also suggested a role for compounds of the invention inpreventing and disrupting initiation of tumor angiogenesis. Inparticular the compounds of the invention may be useful in the treatmentof cancer, metastasis, leukemia's such as CLL, ocular diseases such asage-related macular degeneration in particular wet form of age-relatedmacular degeneration, ischemic proliferative retinopathies such asretinopathy of prematurity (ROP) and diabetic retinopathy, rheumatoidarthritis and hemangioma.

The activity of the compounds of the invention as inhibitors of FGFR1-4,VEGFR and/or PDGFR A/B can be measured using the assays set forth in theexamples below and the level of activity exhibited by a given compoundcan be defined in terms of the IC₅₀ value. Preferred compounds of thepresent invention are compounds having an IC₅₀ value of less than 1 μM,more preferably less than 0.1 μM.

The invention provides compounds that have FGFR inhibiting or modulatingactivity, and which may be useful in preventing or treating diseasestates or conditions mediated by FGFR kinases.

In one embodiment, there is provided a compound as defined herein foruse in therapy, for use as a medicine. In a further embodiment, there isprovided a compound as defined herein for use in the prophylaxis ortreatment, in particular in the treatment, of a disease state orcondition mediated by a FGFR kinase.

Thus, for example, the compounds of the invention may be useful inalleviating or reducing the incidence of cancer. Therefore, in a furtherembodiment, there is provided a compound as defined herein for use inthe prophylaxis or treatment, in particular the treatment, of cancer. Inone embodiment, the compound as defined herein is for use in theprophylaxis or treatment of FGFR-dependent cancer. In one embodiment,the compound as defined herein is for use in the prophylaxis ortreatment of cancer mediated by FGFR kinases.

Accordingly, the invention provides inter alia:

-   -   A method for the prophylaxis or treatment of a disease state or        condition mediated by a FGFR kinase, which method comprises        administering to a subject in need thereof a compound of the        formula (I) as defined herein.    -   A method for the prophylaxis or treatment of a disease state or        condition as described herein, which method comprises        administering to a subject in need thereof a compound of the        formula (I) as defined herein.    -   A method for the prophylaxis or treatment of cancer, which        method comprises administering to a subject in need thereof a        compound of the formula (I) as defined herein.    -   A method for alleviating or reducing the incidence of a disease        state or condition mediated by a FGFR kinase, which method        comprises administering to a subject in need thereof a compound        of the formula (I) as defined herein.    -   A method of inhibiting a FGFR kinase, which method comprises        contacting the kinase with a kinase-inhibiting compound of the        formula (I) as defined herein.    -   A method of modulating a cellular process (for example cell        division) by inhibiting the activity of a FGFR kinase using a        compound of the formula (I) as defined herein.    -   A compound of formula (I) as defined herein for use as a        modulator of a cellular process (for example cell division) by        inhibiting the activity of a FGFR kinase.    -   A compound of formula (I) as defined herein for use in the        prophylaxis or treatment of cancer, in particular the treatment        of cancer.    -   A compound of formula (I) as defined herein for use as a        modulator (e.g. inhibitor) of FGFR.    -   The use of a compound of formula (I) as defined herein for the        manufacture of a medicament for the prophylaxis or treatment of        a disease state or condition mediated by a FGFR kinase, the        compound having the formula (I) as defined herein.    -   The use of a compound of formula (I) as defined herein for the        manufacture of a medicament for the prophylaxis or treatment of        a disease state or condition as described herein.    -   The use of a compound of formula (I) as defined herein for the        manufacture of a medicament for the prophylaxis or treatment, in        particular the treatment, of cancer.    -   The use of a compound of formula (I) as defined herein for the        manufacture of a medicament for modulating (e.g. inhibiting) the        activity of FGFR.    -   Use of a compound of formula (I) as defined herein in the        manufacture of a medicament for modulating a cellular process        (for example cell division) by inhibiting the activity of a FGFR        kinase.    -   The use of a compound of the formula (I) as defined herein for        the manufacture of a medicament for prophylaxis or treatment of        a disease or condition characterised by up-regulation of a FGFR        kinase (e.g. FGFR1 or FGFR2 or FGFR3 or FGFR4).    -   The use of a compound of the formula (I) as defined herein for        the manufacture of a medicament for the prophylaxis or treatment        of a cancer, the cancer being one which is characterised by        up-regulation of a FGFR kinase (e.g. FGFR1 or FGFR2 or FGFR3 or        FGFR4).    -   The use of a compound of the formula (I) as defined herein for        the manufacture of a medicament for the prophylaxis or treatment        of cancer in a patient selected from a sub-population possessing        a genetic aberrations of FGFR3 kinase.    -   The use of a compound of the formula (I) as defined herein for        the manufacture of a medicament for the prophylaxis or treatment        of cancer in a patient who has been diagnosed as forming part of        a sub-population possessing a genetic aberrations of FGFR3        kinase.    -   A method for the prophylaxis or treatment of a disease or        condition characterised by up-regulation of a FGFR kinase (e.g.        FGFR1 or FGFR2 or FGFR3 or FGFR4), the method comprising        administering a compound of the formula (I) as defined herein.    -   A method for alleviating or reducing the incidence of a disease        or condition characterised by up-regulation of a FGFR kinase        (e.g. FGFR1 or FGFR2 or FGFR3 or FGFR4), the method comprising        administering a compound of the formula (I) as defined herein.    -   A method for the prophylaxis or treatment of (or alleviating or        reducing the incidence of) cancer in a patient suffering from or        suspected of suffering from cancer; which method comprises (i)        subjecting a patient to a diagnostic test to determine whether        the patient possesses a genetic aberrations of FGFR3 gene;        and (ii) where the patient does possess the said variant,        thereafter administering to the patient a compound of the        formula (I) as defined herein having FGFR3 kinase inhibiting        activity.    -   A method for the prophylaxis or treatment of (or alleviating or        reducing the incidence of) a disease state or condition        characterised by up-regulation of an FGFR kinase (e.g. FGFR1 or        FGFR2 or FGFR3 or FGFR4); which method comprises (i) subjecting        a patient to a diagnostic test to detect a marker characteristic        of up-regulation of a FGFR kinase (e.g. FGFR1 or FGFR2 or FGFR3        or FGFR4) and (ii) where the diagnostic test is indicative of        up-regulation of a FGFR kinase, thereafter administering to the        patient a compound of the formula (I) as defined herein having        FGFR kinase inhibiting activity.

In one embodiment, the disease mediated by FGFR kinases is a oncologyrelated disease (e.g. cancer). In one embodiment, the disease mediatedby FGFR kinases is a non-oncology related disease (e.g. any diseasedisclosed herein excluding cancer). In one embodiment the diseasemediated by FGFR kinases is a condition described herein. In oneembodiment the disease mediated by FGFR kinases is a skeletal conditiondescribed herein. Particular abnormalities in human skeletaldevelopment, include abnormal ossification of cranial sutures(craniosynostosis), Apert (AP) syndrome, Crouzon syndrome, Jackson-Weisssyndrome, Beare-Stevenson cutis gyrate syndrome, Pfeiffer syndrome,achondroplasia and thanatophoric dwarfism (also known as thanatophoricdysplasia).

Mutated Kinases

Drug resistant kinase mutations can arise in patient populations treatedwith kinase inhibitors. These occur, in part, in the regions of theprotein that bind to or interact with the particular inhibitor used intherapy. Such mutations reduce or increase the capacity of the inhibitorto bind to and inhibit the kinase in question. This can occur at any ofthe amino acid residues which interact with the inhibitor or areimportant for supporting the binding of said inhibitor to the target. Aninhibitor that binds to a target kinase without requiring theinteraction with the mutated amino acid residue will likely beunaffected by the mutation and will remain an effective inhibitor of theenzyme.

A study in gastric cancer patient samples showed the presence of twomutations in FGFR2, Ser167Pro in exon IIIa and a splice site mutation940-2A-G in exon IIIc. These mutations are identical to the germlineactivating mutations that cause craniosynotosis syndromes and wereobserved in 13% of primary gastric cancer tissues studied. In additionactivating mutations in FGFR3 were observed in 5% of the patient samplestested and overexpression of FGFRs has been correlated with a poorprognosis in this patient group.

In addition there are chromosomal translocations or point mutations thathave been observed in FGFR which give rise to gain-of-function,over-expressed, or constitutively active biological states.

The compounds of the invention would therefore find particularapplication in relation to cancers which express a mutated moleculartarget such as FGFR. Diagnosis of tumours with such mutations could beperformed using techniques known to a person skilled in the art and asdescribed herein such as RTPCR and FISH.

It has been suggested that mutations of a conserved threonine residue atthe ATP binding site of FGFR would result in inhibitor resistance. Theamino acid valine 561 has been mutated to a methionine in FGFR1 whichcorresponds to previously reported mutations found in Abl (T315) andEGFR (T766) that have been shown to confer resistance to selectiveinhibitors. Assay data for FGFR1 V561M showed that this mutationconferred resistance to a tyrosine kinase inhibitor compared to that ofthe wild type.

Methods of Diagnosis

Prior to administration of a compound of the formula (I), a patient maybe screened to determine whether a disease or condition from which thepatient is or may be suffering is one which would be susceptible totreatment with a compound having activity against FGFR, and/or VEGFR.

For example, a biological sample taken from a patient may be analysed todetermine whether a condition or disease, such as cancer, that thepatient is or may be suffering from is one which is characterised by agenetic abnormality or abnormal protein expression which leads toup-regulation of the levels or activity of FGFR, and/or VEGFR or tosensitisation of a pathway to normal FGFR, and/or VEGFR activity, or toupregulation of these growth factor signalling pathways such as growthfactor ligand levels or growth factor ligand activity or to upregulationof a biochemical pathway downstream of FGFR, and/or VEGFR activation.

Examples of such abnormalities that result in activation orsensitisation of the FGFR, and/or VEGFR signal include loss of, orinhibition of apoptotic pathways, up-regulation of the receptors orligands, or presence of mutant variants of the receptors or ligands e.gPTK variants. Tumours with mutants of FGFR1, FGFR2 or FGFR3 or FGFR4 orup-regulation, in particular over-expression of FGFR1, orgain-of-function mutants of FGFR2 or FGFR3 may be particularly sensitiveto FGFR inhibitors.

For example, point mutations engendering gain-of-function in FGFR2 havebeen identified in a number of conditions. In particular activatingmutations in FGFR2 have been identified in 10% of endometrial tumours.

In addition, genetic aberrations of the FGFR3 receptor tyrosine kinasesuch as chromosomal translocations or point mutations resulting inectopically expressed or deregulated, constitutively active, FGFR3receptors have been identified and are linked to a subset of multiplemyelomas, bladder and cervical carcinomas. A particular mutation T6741of the PDGF receptor has been identified in imatinib-treated patients.In addition, a gene amplification of 8p12-p11.2 was demonstrated in ˜50%of lobular breast cancer (CLC) cases and this was shown to be linkedwith an increased expression of FGFR1. Preliminary studies with siRNAdirected against FGFR1, or a small molecule inhibitor of the receptor,showed cell lines harbouring this amplification to be particularlysensitive to inhibition of this signalling pathway.

Alternatively, a biological sample taken from a patient may be analysedfor loss of a negative regulator or suppressor of FGFR or VEGFR. In thepresent context, the term “loss” embraces the deletion of a geneencoding the regulator or suppressor, the truncation of the gene (forexample by mutation), the truncation of the transcribed product of thegene, or the inactivation of the transcribed product (e.g. by pointmutation) or sequestration by another gene product.

The term up-regulation includes elevated expression or over-expression,including gene amplification (i.e. multiple gene copies) and increasedexpression by a transcriptional effect, and hyperactivity andactivation, including activation by mutations. Thus, the patient may besubjected to a diagnostic test to detect a marker characteristic ofup-regulation of FGFR, and/or VEGFR. The term diagnosis includesscreening. By marker we include genetic markers including, for example,the measurement of DNA composition to identify mutations of FGFR, and/orVEGFR. The term marker also includes markers which are characteristic ofup regulation of FGFR and/or VEGFR, including enzyme activity, enzymelevels, enzyme state (e.g. phosphorylated or not) and mRNA levels of theaforementioned proteins.

The diagnostic tests and screens are typically conducted on a biologicalsample selected from tumour biopsy samples, blood samples (isolation andenrichment of shed tumour cells), stool biopsies, sputum, chromosomeanalysis, pleural fluid, peritoneal fluid, buccal spears, biopsy orurine.

Methods of identification and analysis of mutations and up-regulation ofproteins are known to a person skilled in the art. Screening methodscould include, but are not limited to, standard methods such asreverse-transcriptase polymerase chain reaction (RT-PCR) or in-situhybridization such as fluorescence in situ hybridization (FISH).

Identification of an individual carrying a mutation in FGFR, and/orVEGFR may mean that the patient would be particularly suitable fortreatment with a FGFR, and/or VEGFR inhibitor. Tumours maypreferentially be screened for presence of a FGFR, and/or VEGFR variantprior to treatment. The screening process will typically involve directsequencing, oligonucleotide microarray analysis, or a mutant specificantibody. In addition, diagnosis of tumours with such mutations could beperformed using techniques known to a person skilled in the art and asdescribed herein such as RT-PCR and FISH.

In addition, mutant forms of, for example FGFR or VEGFR2, can beidentified by direct sequencing of, for example, tumour biopsies usingPCR and methods to sequence PCR products directly as hereinbeforedescribed. The skilled artisan will recognize that all such well-knowntechniques for detection of the over expression, activation or mutationsof the aforementioned proteins could be applicable in the present case.

In screening by RT-PCR, the level of mRNA in the tumour is assessed bycreating a cDNA copy of the mRNA followed by amplification of the cDNAby PCR. Methods of PCR amplification, the selection of primers, andconditions for amplification, are known to a person skilled in the art.Nucleic acid manipulations and PCR are carried out by standard methods,as described for example in Ausubel, F. M. et al., eds. (2004) CurrentProtocols in Molecular Biology, John Wiley & Sons Inc., or Innis, M. A.et al., eds. (1990) PCR Protocols: a guide to methods and applications,Academic Press, San Diego. Reactions and manipulations involving nucleicacid techniques are also described in Sambrook et al., (2001), 3^(rd)Ed, Molecular Cloning: A Laboratory Manual, Cold Spring HarborLaboratory Press. Alternatively a commercially available kit for RT-PCR(for example Roche Molecular Biochemicals) may be used, or methodologyas set forth in U.S. Pat. Nos. 4,666,828; 4,683,202; 4,801,531;5,192,659, 5,272,057, 5,882,864, and 6,218,529 and incorporated hereinby reference. An example of an in-situ hybridisation technique forassessing mRNA expression would be fluorescence in-situ hybridisation(FISH) (see Angerer (1987) Meth. Enzymol., 152: 649).

Generally, in situ hybridization comprises the following major steps:(1) fixation of tissue to be analyzed; (2) prehybridization treatment ofthe sample to increase accessibility of target nucleic acid, and toreduce nonspecific binding; (3) hybridization of the mixture of nucleicacids to the nucleic acid in the biological structure or tissue; (4)post-hybridization washes to remove nucleic acid fragments not bound inthe hybridization, and (5) detection of the hybridized nucleic acidfragments. The probes used in such applications are typically labelled,for example, with radioisotopes or fluorescent reporters. Preferredprobes are sufficiently long, for example, from about 50, 100, or 200nucleotides to about 1000 or more nucleotides, to enable specifichybridization with the target nucleic acid(s) under stringentconditions. Standard methods for carrying out FISH are described inAusubel, F. M. et al., eds. (2004) Current Protocols in MolecularBiology, John Wiley & Sons Inc and Fluorescence In Situ Hybridization:Technical Overview by John M. S. Bartlett in Molecular Diagnosis ofCancer, Methods and Protocols, 2nd ed.; ISBN: 1-59259-760-2; March 2004,pps. 077-088; Series: Methods in Molecular Medicine.

Methods for gene expression profiling are described by (DePrimo et al.(2003), BMC Cancer, 3:3). Briefly, the protocol is as follows:double-stranded cDNA is synthesized from total RNA Using a (dT)24oligomer for priming first-strand cDNA synthesis, followed by secondstrand cDNA synthesis with random hexamer primers. The double-strandedcDNA is used as a template for in vitro transcription of cRNA usingbiotinylated ribonucleotides. cRNA is chemically fragmented according toprotocols described by Affymetrix (Santa Clara, Calif., USA), and thenhybridized overnight on Human Genome Arrays.

Alternatively, the protein products expressed from the mRNAs may beassayed by immunohistochemistry of tumour samples, solid phaseimmunoassay with microtitre plates, Western blotting, 2-dimensionalSDS-polyacrylamide gel electrophoresis, ELISA, flow cytometry and othermethods known in the art for detection of specific proteins.

Detection methods would include the use of site specific antibodies. Theskilled person will recognize that all such well-known techniques fordetection of upregulation of FGFR, and/or VEGFR, or detection of FGFR,and/or VEGFR variants or mutants could be applicable in the presentcase.

Abnormal levels of proteins such as FGFR or VEGFR can be measured usingstandard enzyme assays, for example, those assays described herein.Activation or overexpression could also be detected in a tissue sample,for example, a tumour tissue. By measuring the tyrosine kinase activitywith an assay such as that from Chemicon International. The tyrosinekinase of interest would be immunoprecipitated from the sample lysateand its activity measured.

Alternative methods for the measurement of the over expression oractivation of FGFR or VEGFR including the isoforms thereof, include themeasurement of microvessel density. This can for example be measuredusing methods described by Orre and Rogers (Int J Cancer (1999), 84(2)101-8). Assay methods also include the use of markers, for example, inthe case of VEGFR these include CD31, CD34 and CD105.

Therefore all of these techniques could also be used to identify tumoursparticularly suitable for treatment with the compounds of the invention.

The compounds of the invention are particular useful in treatment of apatient having a mutated FGFR. The G697C mutation in FGFR3 is observedin 62% of oral squamous cell carcmonas and causes constitutiveactivation of the kinase activity. Activating mutations of FGFR3 havealso been identified in bladder carcinoma cases. These mutations were of6 kinds with varying degrees of prevelence: R248C, S249C, G372C, S373C,Y375C, K652Q. In addition, a Gly388Arg polymorphism in FGFR4 has beenfound to be associated with increased incidence and aggressiveness ofprostate, colon, lung, liver (HCC) and breast cancer.

Therefore in a further aspect the invention includes use of a compoundaccording to the invention for the manufacture of a medicament for thetreatment or prophylaxis of a disease state or condition in a patientwho has been screened and has been determined as suffering from, orbeing at risk of suffering from, a disease or condition which would besusceptible to treatment with a compound having activity against FGFR.Particular mutations a patient is screened for include G697C, R248C,S249C, G372C, S373C, Y375C, K652Q mutations in FGFR3 and Gly388Argpolymorphism in FGFR4.

In another aspect the invention includes a compound of the invention foruse in the prophylaxis or treatment of cancer in a patient selected froma sub-population possessing a variant of the FGFR gene (for exampleG697C mutation in FGFR3 and Gly388Arg polymorphism in FGFR4).

MRI determination of vessel normalization (e.g. using MRI gradient echo,spin echo, and contrast enhancement to measure blood volume, relativevessel size, and vascular permeability) in combination with circulatingbiomarkers (circulating progenitor cells (CPCs), CECs, SDF1, and FGF2)may also be used to identify VEGFR2-resistant tumours for treatment witha compound of the invention.

Pharmaceutical Compositions and Combinations

In view of their useful pharmacological properties, the subjectcompounds may be formulated into various pharmaceutical forms foradministration purposes.

In one embodiment the pharmaceutical composition (e.g. formulation)comprises at least one active compound of the invention together withone or more pharmaceutically acceptable carriers, adjuvants, excipients,diluents, fillers, buffers, stabilisers, preservatives, lubricants, orother materials well known to those skilled in the art and optionallyother therapeutic or prophylactic agents.

To prepare the pharmaceutical compositions of this invention, aneffective amount of a compound of the present invention, as the activeingredient is combined in intimate admixture with a pharmaceuticallyacceptable carrier, which carrier may take a wide variety of formsdepending on the form of preparation desired for administration. Thepharmaceutical compositions can be in any form suitable for oral,parenteral, topical, intranasal, ophthalmic, otic, rectal,intra-vaginal, or transdermal administration. These pharmaceuticalcompositions are desirably in unitary dosage form suitable, preferably,for administration orally, rectally, percutaneously, or by parenteralinjection. For example, in preparing the compositions in oral dosageform, any of the usual pharmaceutical media may be employed, such as,for example, water, glycols, oils, alcohols and the like in the case oforal liquid preparations such as suspensions, syrups, elixirs andsolutions; or solid carriers such as starches, sugars, kaolin,lubricants, binders, disintegrating agents and the like in the case ofpowders, pills, capsules and tablets.

Because of their ease in administration, tablets and capsules representthe most advantageous oral dosage unit form, in which case solidpharmaceutical carriers are obviously employed. For parenteralcompositions, the carrier will usually comprise sterile water, at leastin large part, though other ingredients, to aid solubility for example,may be included. Injectable solutions, for example, may be prepared inwhich the carrier comprises saline solution, glucose solution or amixture of saline and glucose solution. Injectable suspensions may alsobe prepared in which case appropriate liquid carriers, suspending agentsand the like may be employed. In the compositions suitable forpercutaneous administration, the carrier optionally comprises apenetration enhancing agent and/or a suitable wetting agent, optionallycombined with suitable additives of any nature in minor proportions,which additives do not cause a significant deleterious effect to theskin. Said additives may facilitate the administration to the skinand/or may be helpful for preparing the desired compositions. Thesecompositions may be administered in various ways, e.g., as a transdermalpatch, as a spot-on, as an ointment. It is especially advantageous toformulate the aforementioned pharmaceutical compositions in dosage unitform for ease of administration and uniformity of dosage. Dosage unitform as used in the specification and claims herein refers to physicallydiscrete units suitable as unitary dosages, each unit containing apredetermined quantity of active ingredient calculated to produce thedesired therapeutic effect in association with the requiredpharmaceutical carrier. Examples of such dosage unit forms are tablets(including scored or coated tablets), capsules, pills, powder packets,wafers, injectable solutions or suspensions, teaspoonfuls,tablespoonfuls and the like, and segregated multiples thereof.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in dosage unit form for ease ofadministration and uniformity of dosage. Dosage unit form as used in thespecification and claims herein refers to physically discrete unitssuitable as unitary dosages, each unit containing a predeterminedquantity of active ingredient, calculated to produce the desiredtherapeutic effect, in association with the required pharmaceuticalcarrier. Examples of such dosage unit forms are tablets (includingscored or coated tablets), capsules, pills, powder packets, wafers,injectable solutions or suspensions, teaspoonfuls, tablespoonfuls andthe like, and segregated multiples thereof.

The compound of the invention is administered in an amount sufficient toexert its anti-tumour activity.

Those skilled in the art could easily determine the effective amountfrom the test results presented hereinafter. In general it iscontemplated that a therapeutically effective amount would be from 0.005mg/kg to 100 mg/kg body weight, and in particular from 0.005 mg/kg to 10mg/kg body weight. It may be appropriate to administer the required doseas single, two, three, four or more sub-doses at appropriate intervalsthroughout the day. Said sub-doses may be formulated as unit dosageforms, for example, containing 0.5 to 500 mg, in particular 1 mg to 500mg, more in particular 10 mg to 500 mg of active ingredient per unitdosage form.

Depending on the mode of administration, the pharmaceutical compositionwill preferably comprise from 0.05 to 99% by weight, more preferablyfrom 0.1 to 70% by weight, even more preferably from 0.1 to 50% byweight of the compound of the present invention, and, from 1 to 99.95%by weight, more preferably from 30 to 99.9% by weight, even morepreferably from 50 to 99.9% by weight of a pharmaceutically acceptablecarrier, all percentages being based on the total weight of thecomposition.

As another aspect of the present invention, a combination of a compoundof the present invention with another anticancer agent is envisaged,especially for use as a medicine, more specifically for use in thetreatment of cancer or related diseases.

For the treatment of the above conditions, the compounds of theinvention may be advantageously employed in combination with one or moreother medicinal agents, more particularly, with other anti-cancer agentsor adjuvants in cancer therapy.

Examples of anti-cancer agents or adjuvants (supporting agents in thetherapy) include but are not limited to:

-   -   platinum coordination compounds for example cisplatin optionally        combined with amifostine, carboplatin or oxaliplatin;    -   taxane compounds for example paclitaxel, paclitaxel protein        bound particles (Abraxane™) or docetaxel;    -   topoisomerase I inhibitors such as camptothecin compounds for        example irinotecan, SN-38, topotecan, topotecan hcl;    -   topoisomerase II inhibitors such as anti-tumour        epipodophyllotoxins or podophyllotoxin derivatives for example        etoposide, etoposide phosphate or teniposide;    -   anti-tumour vinca alkaloids for example vinblastine, vincristine        or vinorelbine;    -   anti-tumour nucleoside derivatives for example 5-fluorouracil,        leucovorin, gemcitabine, gemcitabine hcl, capecitabine,        cladribine, fludarabine, nelarabine;    -   alkylating agents such as nitrogen mustard or nitrosourea for        example cyclophosphamide, chlorambucil, carmustine, thiotepa,        mephalan (melphalan), lomustine, altretamine, busulfan,        dacarbazine, estramustine, ifosfamide optionally in combination        with mesna, pipobroman, procarbazine, streptozocin,        telozolomide, uracil;    -   anti-tumour anthracycline derivatives for example daunorubicin,        doxorubicin optionally in combination with dexrazoxane, doxil,        idarubicin, mitoxantrone, epirubicin, epirubicin hcl,        valrubicin;    -   molecules that target the IGF-1 receptor for example        picropodophilin;    -   tetracarcin derivatives for example tetrocarcin A;    -   glucocorticoïden for example prednisone;    -   antibodies for example trastuzumab (HER2 antibody), rituximab        (CD20 antibody), gemtuzumab, gemtuzumab ozogamicin, cetuximab,        pertuzumab, bevacizumab, alemtuzumab, eculizumab, ibritumomab        tiuxetan, nofetumomab, panitumumab, tositumomab, ONTO 328;    -   estrogen receptor antagonists or selective estrogen receptor        modulators or inhibitors of estrogen synthesis for example        tamoxifen, fulvestrant, toremifene, droloxifene, faslodex,        raloxifene or letrozole;    -   aromatase inhibitors such as exemestane, anastrozole, letrazole,        testolactone and vorozole;    -   differentiating agents such as retinoids, vitamin D or retinoic        acid and retinoic acid metabolism blocking agents (RAM BA) for        example accutane;    -   DNA methyl transferase inhibitors for example azacytidine or        decitabine;    -   antifolates for example premetrexed disodium;    -   antibiotics for example antinomycin D, bleomycin, mitomycin C,        dactinomycin, carminomycin, daunomycin, levamisole, plicamycin,        mithramycin;    -   antimetabolites for example clofarabine, aminopterin, cytosine        arabinoside or methotrexate, azacitidine, cytarabine,        floxuridine, pentostatin, thioguanine;    -   apoptosis inducing agents and antiangiogenic agents such as        Bcl-2 inhibitors for example YC 137, BH 312, ABT 737, gossypol,        HA 14-1, TW 37 or decanoic acid;    -   tubuline-binding agents for example combrestatin, colchicines or        nocodazole;    -   kinase inhibitors (e.g. EGFR (epithelial growth factor receptor)        inhibitors, MTKI (multi target kinase inhibitors), mTOR        inhibitors) for example flavoperidol, imatinib mesylate,        erlotinib, gefitinib, dasatinib, lapatinib, lapatinib        ditosylate, sorafenib, sunitinib, sunitinib maleate,        temsirolimus;    -   farnesyltransferase inhibitors for example tipifarnib;    -   histone deacetylase (HDAC) inhibitors for example sodium        butyrate, suberoylanilide hydroxamide acid (SAHA), depsipeptide        (FR 901228), NVP-LAQ824, R306465, JNJ-26481585, trichostatin A,        vorinostat;    -   Inhibitors of the ubiquitin-proteasome pathway for example        PS-341, MLN 0.41 or bortezomib;    -   Yondelis;    -   Telomerase inhibitors for example telomestatin;    -   Matrix metalloproteinase inhibitors for example batimastat,        marimastat, prinostat or metastat.    -   Recombinant interleukins for example aldesleukin, denileukin        diftitox, interferon alfa 2a, interferon alfa 2b, peginterferon        alfa 2b    -   MAPK inhibitors    -   Retinoids for example alitretinoin, bexarotene, tretinoin    -   Arsenic trioxide    -   Asparaginase    -   Steroids for example dromostanolone propionate, megestrol        acetate, nandrolone (decanoate, phenpropionate), dexamethasone    -   Gonadotropin releasing hormone agonists or antagonists for        example abarelix, goserelin acetate, histrelin acetate,        leuprolide acetate    -   Thalidomide, lenalidomide    -   Mercaptopurine, mitotane, pamidronate, pegademase, pegaspargase,        rasburicase    -   BH3 mimetics for example ABT-737    -   MEK inhibitors for example PD98059, AZD6244, CI-1040    -   colony-stimulating factor analogs for example filgrastim,        pegfilgrastim, sargramostim; erythropoietin or analogues thereof        (e.g. darbepoetin alfa); interleukin 11; oprelvekin;        zoledronate, zoledronic acid; fentanyl; bisphosphonate;        palifermin.    -   a steroidal cytochrome P450 17alpha-hydroxylase-17,20-lyase        inhibitor (CYP17), e.g. abiraterone, abiraterone acetate.

The compounds of the present invention also have therapeuticapplications in sensitising tumour cells for radiotherapy andchemotherapy.

Hence the compounds of the present invention can be used as“radiosensitizer” and/or “chemosensitizer” or can be given incombination with another “radiosensitizer” and/or “chemosensitizer”.

The term “radiosensitizer”, as used herein, is defined as a molecule,preferably a low molecular weight molecule, administered to animals intherapeutically effective amounts to increase the sensitivity of thecells to ionizing radiation and/or to promote the treatment of diseaseswhich are treatable with ionizing radiation.

The term “chemosensitizer”, as used herein, is defined as a molecule,preferably a low molecular weight molecule, administered to animals intherapeutically effective amounts to increase the sensitivity of cellsto chemotherapy and/or promote the treatment of diseases which aretreatable with chemotherapeutics.

Several mechanisms for the mode of action of radiosensitizers have beensuggested in the literature including: hypoxic cell radiosensitizers(e.g., 2-nitroimidazole compounds, and benzotriazine dioxide compounds)mimicking oxygen or alternatively behave like bioreductive agents underhypoxia; non-hypoxic cell radiosensitizers (e.g., halogenatedpyrimidines) can be analogues of DNA bases and preferentiallyincorporate into the DNA of cancer cells and thereby promote theradiation-induced breaking of DNA molecules and/or prevent the normalDNA repair mechanisms; and various other potential mechanisms of actionhave been hypothesized for radiosensitizers in the treatment of disease.

Many cancer treatment protocols currently employ radiosensitizers inconjunction with radiation of x-rays. Examples of x-ray activatedradiosensitizers include, but are not limited to, the following:metronidazole, misonidazole, desmethylmisonidazole, pimonidazole,etanidazole, nimorazole, mitomycin C, RSU 1069, SR 4233, EO9, RB 6145,nicotinamide, 5-bromodeoxyuridine (BUdR), 5-iododeoxyuridine (IUdR),bromodeoxycytidine, fluorodeoxyuridine (FudR), hydroxyurea, cisplatin,and therapeutically effective analogs and derivatives of the same.

Photodynamic therapy (PDT) of cancers employs visible light as theradiation activator of the sensitizing agent. Examples of photodynamicradiosensitizers include the following, but are not limited to:hematoporphyrin derivatives, Photofrin, benzoporphyrin derivatives, tinetioporphyrin, pheoborbide-a, bacteriochlorophyll-a, naphthalocyanines,phthalocyanines, zinc phthalocyanine, and therapeutically effectiveanalogs and derivatives of the same.

Radiosensitizers may be administered in conjunction with atherapeutically effective amount of one or more other compounds,including but not limited to: compounds which promote the incorporationof radiosensitizers to the target cells; compounds which control theflow of therapeutics, nutrients, and/or oxygen to the target cells;chemotherapeutic agents which act on the tumour with or withoutadditional radiation; or other therapeutically effective compounds fortreating cancer or other diseases.

Chemosensitizers may be administered in conjunction with atherapeutically effective amount of one or more other compounds,including but not limited to: compounds which promote the incorporationof chemosensitizers to the target cells; compounds which control theflow of therapeutics, nutrients, and/or oxygen to the target cells;chemotherapeutic agents which act on the tumour or other therapeuticallyeffective compounds for treating cancer or other disease. Calciumantagonists, for example verapamil, are found useful in combination withantineoplastic agents to establish chemosensitivity in tumor cellsresistant to accepted chemotherapeutic agents and to potentiate theefficacy of such compounds in drug-sensitive malignancies.

In view of their useful pharmacological properties, the components ofthe combinations according to the invention, i.e. the one or more othermedicinal agent and the compound according to the present invention maybe formulated into various pharmaceutical forms for administrationpurposes. The components may be formulated separately in individualpharmaceutical compositions or in a unitary pharmaceutical compositioncontaining all components.

The present invention therefore also relates to a pharmaceuticalcomposition comprising the one or more other medicinal agent and thecompound according to the present invention together with apharmaceutical carrier.

The present invention further relates to the use of a combinationaccording to the invention in the manufacture of a pharmaceuticalcomposition for inhibiting the growth of tumour cells.

The present invention further relates to a product containing as firstactive ingredient a compound according to the invention and as furtheractive ingredient one or more anticancer agent, as a combinedpreparation for simultaneous, separate or sequential use in thetreatment of patients suffering from cancer.

The one or more other medicinal agents and the compound according to thepresent invention may be administered simultaneously (e.g. in separateor unitary compositions) or sequentially in either order. In the lattercase, the two or more compounds will be administered within a period andin an amount and manner that is sufficient to ensure that anadvantageous or synergistic effect is achieved. It will be appreciatedthat the preferred method and order of administration and the respectivedosage amounts and regimes for each component of the combination willdepend on the particular other medicinal agent and compound of thepresent invention being administered, their route of administration, theparticular tumour being treated and the particular host being treated.The optimum method and order of administration and the dosage amountsand regime can be readily determined by those skilled in the art usingconventional methods and in view of the information set out herein.

The weight ratio of the compound according to the present invention andthe one or more other anticancer agent(s) when given as a combinationmay be determined by the person skilled in the art. Said ratio and theexact dosage and frequency of administration depends on the particularcompound according to the invention and the other anticancer agent(s)used, the particular condition being treated, the severity of thecondition being treated, the age, weight, gender, diet, time ofadministration and general physical condition of the particular patient,the mode of administration as well as other medication the individualmay be taking, as is well known to those skilled in the art.Furthermore, it is evident that the effective daily amount may belowered or increased depending on the response of the treated subjectand/or depending on the evaluation of the physician prescribing thecompounds of the instant invention. A particular weight ratio for thepresent compound of formula (I) and another anticancer agent may rangefrom 1/10 to 10/1, more in particular from 1/5 to 5/1, even more inparticular from 1/3 to 3/1.

The platinum coordination compound is advantageously administered in adosage of 1 to 500 mg per square meter (mg/m²) of body surface area, forexample 50 to 400 mg/m², particularly for cisplatin in a dosage of about75 mg/m² and for carboplatin in about 300 mg/m² per course of treatment.

The taxane compound is advantageously administered in a dosage of 50 to400 mg per square meter (mg/m²) of body surface area, for example 75 to250 mg/m², particularly for paclitaxel in a dosage of about 175 to 250mg/m² and for docetaxel in about 75 to 150 mg/m² per course oftreatment.

The camptothecin compound is advantageously administered in a dosage of0.1 to 400 mg per square meter (mg/m²) of body surface area, for example1 to 300 mg/m², particularly for irinotecan in a dosage of about 100 to350 mg/m² and for topotecan in about 1 to 2 mg/m² per course oftreatment.

The anti-tumour podophyllotoxin derivative is advantageouslyadministered in a dosage of 30 to 300 mg per square meter (mg/m²) ofbody surface area, for example 50 to 250 mg/m², particularly foretoposide in a dosage of about 35 to 100 mg/m² and for teniposide inabout 50 to 250 mg/m² per course of treatment.

The anti-tumour vinca alkaloid is advantageously administered in adosage of 2 to 30 mg per square meter (mg/m²) of body surface area,particularly for vinblastine in a dosage of about 3 to 12 mg/m², forvincristine in a dosage of about 1 to 2 mg/m², and for vinorelbine indosage of about 10 to 30 mg/m² per course of treatment.

The anti-tumour nucleoside derivative is advantageously administered ina dosage of 200 to 2500 mg per square meter (mg/m²) of body surfacearea, for example 700 to 1500 mg/m², particularly for 5-FU in a dosageof 200 to 500 mg/m², for gemcitabine in a dosage of about 800 to 1200mg/m² and for capecitabine in about 1000 to 2500 mg/m² per course oftreatment.

The alkylating agents such as nitrogen mustard or nitrosourea isadvantageously administered in a dosage of 100 to 500 mg per squaremeter (mg/m²) of body surface area, for example 120 to 200 mg/m²,particularly for cyclophosphamide in a dosage of about 100 to 500 mg/m²,for chlorambucil in a dosage of about 0.1 to 0.2 mg/kg, for carmustinein a dosage of about 150 to 200 mg/m², and for lomustine in a dosage ofabout 100 to 150 mg/m² per course of treatment.

The anti-tumour anthracycline derivative is advantageously administeredin a dosage of 10 to 75 mg per square meter (mg/m²) of body surfacearea, for example 15 to 60 mg/m², particularly for doxorubicin in adosage of about 40 to 75 mg/m², for daunorubicin in a dosage of about 25to 45 mg/m², and for idarubicin in a dosage of about 10 to 15 mg/m² percourse of treatment.

The antiestrogen agent is advantageously administered in a dosage ofabout 1 to 100 mg daily depending on the particular agent and thecondition being treated. Tamoxifen is advantageously administered orallyin a dosage of 5 to 50 mg, preferably 10 to 20 mg twice a day,continuing the therapy for sufficient time to achieve and maintain atherapeutic effect. Toremifene is advantageously administered orally ina dosage of about 60 mg once a day, continuing the therapy forsufficient time to achieve and maintain a therapeutic effect.Anastrozole is advantageously administered orally in a dosage of about 1mg once a day. Droloxifene is advantageously administered orally in adosage of about 20-100 mg once a day. Raloxifene is advantageouslyadministered orally in a dosage of about 60 mg once a day. Exemestane isadvantageously administered orally in a dosage of about 25 mg once aday.

Antibodies are advantageously administered in a dosage of about 1 to 5mg per square meter (mg/m²) of body surface area, or as known in theart, if different. Trastuzumab is advantageously administered in adosage of 1 to 5 mg per square meter (mg/m²) of body surface area,particularly 2 to 4 mg/m² per course of treatment. These dosages may beadministered for example once, twice or more per course of treatment,which may be repeated for example every 7, 14, 21 or 28 days.

The compounds of formula (I), the pharmaceutically acceptable additionsalts, in particular pharmaceutically acceptable acid addition salts,and stereoisomeric forms thereof can have valuable diagnostic propertiesin that they can be used for detecting or identifying the formation of acomplex between a labelled compound and other molecules, peptides,proteins, enzymes or receptors.

The detecting or identifying methods can use compounds that are labelledwith labelling agents such as radioisotopes, enzymes, fluorescentsubstances, luminous substances, etc. Examples of the radioisotopesinclude ¹²⁵I, ¹³¹I, ³H and ¹⁴C. Enzymes are usually made detectable byconjugation of an appropriate substrate which, in turn catalyses adetectable reaction. Examples thereof include, for example,beta-galactosidase, beta-glucosidase, alkaline phosphatase, peroxidaseand malate dehydrogenase, preferably horseradish peroxidase. Theluminous substances include, for example, luminol, luminol derivatives,luciferin, aequorin and luciferase.

Biological samples can be defined as body tissue or body fluids.Examples of body fluids are cerebrospinal fluid, blood, plasma, serum,urine, sputum, saliva and the like.

General Synthetic Routes

The following examples illustrate the present invention but are examplesonly and are not intended to limit the scope of the claims in any way.

The values of salt stoichiometry or acid content in the compounds asprovided herein, are those obtained experimentally and may varydependent on the analytical method used (NMR for compounds 61′, 62′ and73′). In case no salt form is indicated, the compound was obtained as afree base.

Hereinafter, the term ‘DCM’ means dichloromethane, ‘Me’ means methyl,‘Et’ means ethyl, ‘MeOH’ means methanol, ‘DMF’ means dimethylformamide,‘Et₂O’ means diethyl ether, ‘EtOAc’ means ethyl acetate, Brettphospalladacycle: (CAS: 1148148-01-9) meansChloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2′-4′-6′-tri-i-propyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl]palladium(II),‘PdCl₂dppf’ (CAS: 72287-26-4) means 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium (II), ‘THF’ means tetrahydrofuran, ‘ACN’ meansacetonitrile, ‘SFC’ means supercritical fluid chromatography, ‘MgSO₄’means magnesium sulfate, ‘q.s.’ means quantum sufficit, ‘MP’ meansmelting point, ‘iPrNH₂’ means isopropylamine, ‘DSC’ means differentialscanning calorimetry, ‘DIPE’ means diisopropylether, ‘TBAF’ meanstetrabutylammonium fluoride, ‘rt’ means room temperature, ‘Pd₂dba₃ meanstris(dibenzylideneacetone)dipalladium(0), ‘BINAP’ means[1,1′-binaphthalene]-2,2′-diylbis[diphenylphosphine].

A. Preparation of the Intermediate Compounds Example A1 Preparation ofIntermediate 1

2-Amino-5-bromobenzoic acid (50 g; 231.4 mmol) was dissolved in toluene(500 mL). Triethyl orthoformate was added (58 mL; 347.2 mmol) followedby acetic acid (1.3 mL; 23.1 mmol). The mixture was heated at 110° C.for 2.5 hours. The reaction was cooled to room temperature and aniline(21 mL; 231.4 mmol) was added. The mixture was heated at 110° C. foranother 20 hours. The resulting mixture was cooled at room temperatureand filtered. The filtrate was crystallized from petroleum ether. Theprecipitate was filtered and recrystallized from a mixture of DCM andpetroleum ether to afford 15.6 g (22%) of intermediate 1.

MP=178° C.

Preparation of Intermediate 2

A mixture of intermediate 1 (1.4 g; 4.6 mmol),2,6-difluoro-3,5-dimethoxyaniline (1.3 g; 6.9 mmol), Brettphospalladacycle (0.18 g; 0.23 mmol) and cesium carbonate (4.5 g; 13.75mmol) in toluene (60 mL) was heated at 100° C. for 5 hours. The mixturewas cooled, poured onto cooled water and DCM was added. The solution wasfiltered through a pad of Celite® and the filtrate was extracted withDCM. The organic layer was dried over MgSO₄, filtered and evaporated todryness.

The residue (2.4 g) was purified by chromatography over silica gel(irregular SiOH 50 g; mobile phase: 99% DCM, 1% MeOH). The fractionscontaining the product were collected and evaporated to dryness yielding2.1 g of an intermediate compound which was crystallized from a mixtureof MeOH and Et₂O to afford 704 mg (38%) of intermediate 2.

MP=156° C. (DSC)

Preparation of Intermediate 5

Intermediate 5 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 2, using2,6-dichloro-3,5-dimethoxyaniline as starting material (yield: 59%).

Preparation of Intermediate 7

Intermediate 7 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 2, using2-fluoro-3,5-dimethoxyaniline as starting material (yield: 52%).

Preparation of Intermediate 9

Intermediate 9 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 2, using3,5-dimethoxyaniline as starting material (yield: 45%).

Example A2 Preparation of Intermediate 3

Under N₂ at 10° C., sodium hydride (60% in mineral oil) (0.4 g; 9 mmol)was added to a solution of intermediate 2 (1.24 g; 3 mmol) in DMF (12mL). The solution was stirred at 10° C. for 30 minutes. Subsequently, asolution of (2-bromoethoxy)-tert-butyldimethylsilane (1.4 mL; 6.7 mmol)in DMF (3 mL) was added dropwise. The solution was allowed to slowlyrise to room temperature for 5 hours. The solution was poured ontocooled water and the product was extracted with EtOAc. The organic layerwas washed with water, dried over MgSO₄, filtered and evaporated todryness to give 2 g of intermediate 3 which was used as such in the nextreaction step without any further treatment.

Preparation of Intermediate 6

Intermediate 6 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 3, using intermediate 5 asstarting material.

Preparation of Intermediate 8

Intermediate 8 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 3, using intermediate 7 asstarting material.

Preparation of Intermediate 10

Intermediate 10 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 3, using intermediate 9 asstarting material.

Example A3 Preparation of Intermediate 4

Methanesulfonyl chloride (0.3 mL; 3.75 mmol) was added drop wise to asolution of compound 1 (0.43 g; 0.94 mmol) and triethylamine (0.65 mL;4.7 mmol) in DCM (20 mL) at 5° C. under N₂ flow. The reaction mixturewas stirred at 5° C. for 2 hours, then poured onto ice water and DCM(q.s.) was added. The organic layer was separated, dried over MgSO₄,filtered and the solvent was evaporated to dryness at room temperatureto give 0.5 g of intermediate 4 which was directly used as such in thenext reaction step without any further treatment.

Example A4 Preparation of Intermediate 11

2-Amino-5-bromobenzoic acid (33.4 g; 154.4 mmol) was dissolved intoluene (2 L). Triethyl orthoformate was added (34 g; 231.7 mmol)followed by acetic acid (2 mL). The mixture was heated at 110° C. for2.5 hours. The reaction was cooled to room temperature and4-amino-1-methylpyrazole (15 g; 154.4 mmol) was added. The mixture washeated at 110° C. for another 20 hours. The resulting mixture was cooledto room temperature and filtered. The filtrate was crystallized from amixture of toluene and petroleum ether. The precipitate was filtered andpurified by chromatography over silica gel (irregular SiOH; mobilephase: DCM/MeOH 80/1). The fractions containing the product werecollected and evaporated to dryness yielding 11 g (23%) of intermediate11.

Preparation of Intermediate 22

A mixture of intermediate 11 (1.4 g; 4.6 mmol),2,6-difluoro-3,5-dimethoxyaniline (1.4 g; 7.3 mmol), Brettphospalladacycle (0.18 g; 0.23 mmol) and cesium carbonate (4.5 g; 14 mmol)in toluene (60 mL) was heated at 100° C. overnight. The mixture wascooled, poured onto cooled water and EtOAc was added. The solution wasfiltered through a pad of Celite® (diatomaceous earth) and the productwas extracted with EtOAc. The organic layer was dried over MgSO₄,filtered and evaporated to dryness.

The residue (2.6 g) was purified by chromatography over silica gel(irregular SiOH, 300 g; mobile phase: 60% heptane, 5% MeOH, 35% EtOAc).The fractions containing the product were collected and evaporated todryness yielding 1.1 g of an intermediate which was crystallized fromEt₂O yielding 1.06 g (56%) of intermediate 22.

MP=214° C. (DSC)

Preparation of Intermediate 12

Intermediate 12 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 22, using m-anisidine asstarting material (yield: 13%).

Preparation of Intermediate 13

Intermediate 13 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 22, using3,5-dimethoxyaniline as starting material (yield: 50%).

Preparation of Intermediate 16

Intermediate 16 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 22, using2,6-dichloro-3,5-dimethoxyaniline as starting material (yield: 45%).

Preparation of Intermediate 19

Intermediate 19 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 22, using2-fluoro-3,5-dimethoxyaniline as starting material (yield: 7%).

Example A5 Preparation of Intermediate 23

Under N₂ at 10° C., sodium hydride (60% in mineral oil) (0.26 g; 6.4mmol) was added to a solution of intermediate 22 (0.88 g; 2 mmol) in DMF(12 mL). The solution was stirred at 10° C. for 30 minutes. Then, asolution of (2-bromoethoxy)-tert-butyldimethylsilane (1 mL; 4.7 mmol) inDMF (3 mL) was added drop wise. The solution was allowed to slowly riseto room temperature for 5 hours. The solution was poured onto cooledwater and the product was extracted with EtOAc. The organic layer waswashed with water, dried over MgSO₄, filtered and evaporated to drynessgiven 1.65 g of intermediate 23 which was directly used as such in thenext reaction step without any further treatment.

Preparation of Intermediate 14

Intermediate 14 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 23, using intermediate 13 asstarting material.

Preparation of Intermediate 17

Intermediate 17 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 23, using intermediate 16 asstarting material.

Preparation of Intermediate 20

Intermediate 20 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 23, using intermediate 19 asstarting material.

Example A6 Preparation of Intermediate 24

Methanesulfonyl chloride (0.5 mL; 6.4 mmol) was added drop wise to asolution of compound 18 (0.74 g; 1.6 mmol) and triethylamine (1.1 mL; 8mmol) in DCM (10 mL) at 5° C. under N₂ flow. The reaction mixture wasstirred at 5° C. for 2 hours. The reaction mixture was poured onto icedwater and DCM was added. The organic layer was separated, dried overMgSO₄, filtered and the solvent was evaporated to dryness at roomtemperature to give 0.8 g of intermediate 24 which was directly used assuch in the next step without any further treatment.

Preparation of Intermediate 15

Intermediate 15 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 24, using compound 8 asstarting material.

Preparation of Intermediate 18

Intermediate 18 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 24, using compound 10 asstarting material.

Preparation of Intermediate 21

Intermediate 21 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 24, using compound 16 asstarting material.

Example A7 Preparation of Intermediate 25

Intermediate 25 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 1, using4-aminopiperidine-1-carboxylate as starting material (yield: 98%).

Preparation of Intermediate 26

Pd₂dba₃ (224 mg; 0.245 mmol) and BINAP (305 mg; 0.49 mmol) was added toa solution of intermediate 25 (2 g; 4.9 mmol),2,6-difluoro-3,5-dimethoxyaniline (1.39 g; 7.35 mmol) and Cs₂CO₃ (4.79g; 14.69 mmol) in dioxane (60 mL). The reaction mixture was heatedovernight at 80° C. Then, it was poured onto cooled water and theaqueous layer was extracted with DCM. The organic layer was dried overMgSO₄, filtered and the solvent was evaporated. The resulting residuewas crystallized from DIPE to afford 1.90 g of intermediate 26 (75%).

MP=260° C. (Kofler)

Preparation of Intermediate 27

Intermediate 27 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 2, using3,5-dimethoxyaniline and intermediate 25 as starting materials (yield:84%).

MP=241° C. (Kofler)

Preparation of Intermediate 28

Intermediate 28 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 2, using2-fluoro-3,5-dimethoxyaniline and intermediate 25 as starting materials(yield: 70%).

MP=263° C. (Kofler)

Example A8 Preparation of Intermediate 29

Under N₂ at −10° C., sodium hydride (60% in mineral oil) (116 mg; 2.904mmol) was added to a solution of intermediate 26 (500 mg; 0.968 mmol) inDMF (15 mL). The reaction mixture was stirred at −10° C. for 30 minutes.Then, (2-bromoethoxy)-tert-butyldimethylsilane (0.455 mL; 2.13 mmol) wasadded dropwise. The reaction mixture was allowed to warm to roomtemperature over 2 hours. The solution was poured onto ice/water and theproduct was extracted with EtOAc. The organic layer was washed withbrine, dried over MgSO₄, filtered and evaporated to dryness. The residuewas purified by chromatography over silica gel (irregular SiOH, 30 g;mobile phase: gradient from 0% MeOH, 100% DCM to 2% MeOH, 98% DCM). Thefractions containing the product were collected and evaporated todryness yielding 436 mg (67%) of intermediate 29.

Preparation of Intermediate 30

Intermediate 30 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 29, using intermediate 28 asstarting material (yield: 77%).

Preparation of Intermediate 48

Intermediate 48 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 29, using intermediate 27 asstarting material (yield: 64%).

Example A9 Preparation of Intermediate 31

Intermediate 31 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 1, using 3-aminopyridine asstarting material (yield: 24%).

Preparation of Intermediate 32

Intermediate 32 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 2, using2,6-difluoro-3,5-dimethoxyaniline and intermediate 31 as startingmaterials (yield: 51%).

MP=165° C. (Kofler)

Preparation of Intermediate 33

Intermediate 33 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 2, using2-difluoro-3,5-dimethoxyaniline and intermediate 31 as startingmaterials (yield: 23%).

MP=162° C. (Kofler)

Preparation of Intermediate 34

Intermediate 34 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 2, using3,5-dimethoxyaniline and intermediate 31 as starting materials (yield:80%).

MP=176° C. (Kofler)

Example A10 Preparation of Intermediate 35

Intermediate 35 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 23, using intermediate 32 asstarting material. This compound was directly used as such in the nextreaction step without any further treatment.

Preparation of Intermediate 36

Intermediate 36 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 23, using intermediate 33 asstarting material. This compound was directly used as such in the nextreaction step without any further treatment.

Preparation of Intermediate 37

Intermediate 37 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 23, using intermediate 34 asstarting material (yield: 61%).

Example A11 Preparation of Intermediate 38

Intermediate 38 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 24, using compound 29 asstarting material. This compound was directly used as such in the nextreaction step without any further treatment.

Preparation of Intermediate 39

Intermediate 39 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 24, using compound 30 asstarting material. This compound was directly used as such in the nextreaction step without any further treatment.

Preparation of Intermediate 40

Intermediate 40 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 24, using compound 31 asstarting material. This compound was directly used as such in the nextreaction step without any further treatment.

Example A12 Preparation of Intermediate 41

Intermediate 41 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 1, using 4-aminopyridine asstarting material (yield: 29%).

Preparation of Intermediate 42

Intermediate 42 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 2, using2,6-difluoro-3,5-dimethoxyaniline and intermediate 41 as startingmaterials (yield: 19%).

100 mg of intermediate 42 were purified by achiral SFC (Stationaryphase: 2 ethylpyridine 6 μm 150×21.2 mm), Mobile phase: 80% CO₂, 20%MeOH(0.3% iPrNH₂)) to afford 84 mg of intermediate 42 (MP=248° C.(Kofler)).

Preparation of Intermediate 43

Intermediate 43 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 2, using2-difluoro-3,5-dimethoxyaniline and intermediate 41 as startingmaterials (yield: 55%).

150 mg of intermediate 43 was recrystallised from MeOH and DIPE yielding107 mg of intermediate 43 (MP=215° C. (Kofler)).

Preparation of Intermediate 44

Intermediate 44 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 2, using3,5-dimethoxyaniline and intermediate 41 as starting materials (yield:23%).

MP=216° C. (Kofler)

Example A13 Preparation of Intermediate 45

Intermediate 45 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 23, using intermediate 42 asstarting material. This compound was directly used as such in the nextreaction step without any further treatment.

Preparation of Intermediate 46

Intermediate 46 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 23, using intermediate 43 asstarting material. This compound was directly used as such in the nextreaction step without any further treatment.

Preparation of Intermediate 47

Intermediate 47 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 23, using intermediate 44 asstarting material. This compound was directly used as such in the nextreaction step without any further treatment.

Example A14 Preparation of Intermediate 49

Sodium hydride (60% in mineral oil) (116 mg; 2.904 mmol) was added at−10° C. to a solution of intermediate 26 (500 mg; 0.968 mmol) in DMF (15mL). The reaction mixture was stirred at −10° C. for 30 minutes. Then,(3-bromopropoxy)-tert-butyldimethylsilane (0.48 mL; 2.13 mmol) was addeddropwise. The reaction mixture was allowed to warm to 5° C. over 2hours. The solution was poured onto ice/water and the product wasextracted with EtOAc. The organic layer was washed with brine, driedover MgSO₄, filtered and evaporated to dryness. The residue wascrystallized from Et₂O and the precipitate was filtered and driedyielding 347 mg of intermediate 49 (52%).

Preparation of Intermediate 50

Intermediate 50 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 49, using intermediate 28 asstarting material. (yield: 73%)

Preparation of Intermediate 51

Intermediate 51 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 49, using intermediate 27 asstarting material. (yield: 88%)

Example A15 Preparation of Intermediate 52

Intermediate 52 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 24, using compound 25 asstarting material. This compound was directly used as such in the nextreaction step without any further treatment.

Preparation of Intermediate 53

Intermediate 53 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 24, using compound 26 asstarting material. This compound was directly used as such in the nextreaction step without any further treatment.

Preparation of Intermediate 54

Intermediate 54 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 24, using compound 56 asstarting material. This compound was directly used as such in the nextreaction step without any further treatment.

Example A16 Preparation of Intermediate 55

Intermediate 55 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 24, using compound 50 asstarting material. This compound was directly used as such in the nextreaction step without any further treatment.

Preparation of Intermediate 56

Intermediate 56 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 24, using compound 51 asstarting material. This compound was directly used as such in the nextreaction step without any further treatment.

Preparation of Intermediate 57

Intermediate 57 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 24, using compound 52 asstarting material. This compound was directly used as such in the nextreaction step without any further treatment.

Example A17 Preparation of Intermediate 58

2-Amino-5-bromobenzoic acid (30 g; 138.9 mmol), triethyl orthoformate(30.9 g; 208.3 mmol) and acetic acid (0.9 mL) were dissolved in toluene(1.5 L). The mixture was heated at 110° C. for 2.5 hours. Then,tetrahydro-2H-pyran-4-amine (14.05 g; 138.9 mmol) was added and thereaction mixture was refluxed for 3 days. The resulting mixture wascooled at room temperature and filtered. The filtrate was concentratedand crystallized from a mixture of DCM and petroleum ether to afford26.9 g (62%) of intermediate 58.

Preparation of Intermediate 59

Pd₂dba₃ (296 mg; 0.32 mmol) and BINAP (403 mg; 0.65 mmol) were added toa solution of 2-fluoro-3,5-dimethoxyaniline (1.66 g; 9.70 mmol),intermediate 58 (2 g; 6.47 mmol) and Cs₂CO₃ (6.32 g; 19.41 mmol) in1,4-dioxane (80 mL). The mixture was heated at 80° C. overnight. Thesolution was poured onto cooled water, the product was extracted withDCM. The organic layer was washed with brine, dried over MgSO₄, filteredand evaporated to dryness. The residue was crystallized from DIPE. Theprecipitate was filtered to afford an intermediate residue (2.02 gcontaining 81% of intermediate 59 based on LC/MS). 150 mg of thisresidue were purified by flash chromatography over silica gel (15-40 μm,4 g, DCM/MeOH: 98/2). The fractions containing the product werecollected and evaporated to dryness to give 62 mg of intermediate 59.

MP=240° C. (Kofler).

Preparation of Intermediate 60

Intermediate 60 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 2, using3,5-dimethoxyaniline and intermediate 58 as starting materials (yield:85%).

MP=205° C. (Kofler)

Example A18 Preparation of Intermediate 61

Intermediate 61 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 29, using intermediate 59 asstarting material (yield: 31%).

Preparation of Intermediate 62

Intermediate 62 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 29, using intermediate 60 asstarting material (yield: 59%).

Example A19 Preparation of Intermediate 63

Under N₂ at 10° C., sodium hydride (60% in mineral oil) (60 mg; 1.50mmol) was added to a solution of intermediate 59 (200 mg; 0.50 mmol) inDMF (12 mL). The solution was stirred at 10° C. for 30 minutes. Then asolution of (3-bromopropoxy)-tert-butyldimethylsilane (0.26 mL; 1.10mmol) in DMF (3 mL) was added dropwise. The solution was stirred at 10°C. for 5 hours. The solution was poured onto cooled water and theproduct was extracted with EtOAc. The organic layer was washed withbrine, dried over MgSO₄, filtered and evaporated to dryness. The residue(367 mg) was purified by flash chromatography over silica gel (15-40 μm,12 g, DCM/MeOH: 99/1). The fractions containing the product werecollected and evaporated to dryness to give 71 mg (26%) of intermediate63.

Preparation of Intermediate 64

Intermediate 64 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 49, using intermediate 60 asstarting material. This compound was directly used as such in the nextreaction step without any further treatment.

Example A20 Preparation of Intermediate 65

Intermediate 65 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 24, using compound 63 asstarting material. This compound was directly used as such in the nextreaction step without any further treatment.

Preparation of Intermediate 66

Intermediate 66 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 24, using compound 64 asstarting material. This compound was directly used as such in the nextreaction step without any further treatment.

Example A21 Preparation of Intermediate 67

Intermediate 67 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 24, using compound 65 asstarting material. This compound was directly used as such in the nextreaction step without any further treatment.

Preparation of Intermediate 68

Intermediate 68 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 24, using compound 66 asstarting material. This compound was directly used as such in the nextreaction step without any further treatment.

Example A22 Preparation of Intermediate 69

2-Amino-5-bromobenzoic acid (19.8 g; 91.6 mmol) was dissolved in xylene(870 mL). Triethyl orthoformate was added (20.4 g; 137.5 mmol) and themixture was heated at 110° C. for 2.5 hours. The reaction was cooled toroom temperature and 5-amino-pyrimidine (9.51 g; 100 mmol) was added.The mixture was refluxed for another 48 hours. The resulting mixture wascooled at room temperature and evaporated until dryness. The residue wascrystallized from a mixture of methanol and 2-isopropoxypropane and theprecipitate was filtered. The residue was purified by chromatographyover silica gel (mobile phase: gradient from DCM/MeOH 100/1 to 50%DCM/50% MeOH). The fractions containing the product were collected andevaporated to dryness to give 6.1 g (22%) of intermediate 69.

Preparation of Intermediate 70

Intermediate 70 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 2, using2-fluoro-3,5-dimethoxyaniline and intermediate 69 as starting materials.

100 mg of crude intermediate 70 were purified by flash chromatographyover silica gel (15-40 μm, 4 g, DCM/MeOH: 98/2). The fractionscontaining the product were collected and evaporated to dryness to give35 mg of intermediate 70 (MP=225° C. (Kofler))

Preparation of Intermediate 72

Intermediate 72 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 2, using2,6-difluoro-3,5-dimethoxyaniline and intermediate 69 as startingmaterials (yield: 72%).

MP=187° C. (Kofler)

Example A23 Preparation of Intermediate 71

Intermediate 71 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 29, using intermediate 70 asstarting material (yield: 35%).

Preparation of Intermediate 73

Intermediate 73 was prepared according to an analogous procedure asdescribed for the synthesis of intermediate 29, using intermediate 72 asstarting material (yield: 31%).

B. Preparation of the Final Compounds Example B1 Preparation of Compound18

At 10° C., tetrabutylammonium fluoride (13 mL; 43 mmol) was added to asolution of intermediate 23 (1.65 g; 3 mmol) in THF (50 mL) and themixture was stirred at room temperature for 8 hours. The solution waspoured onto cooled water and the product was extracted with EtOAc. Theorganic layer was dried over MgSO₄, filtered and evaporated to dryness.The residue (1.3 g) was purified by chromatography over silica gel(Irregular SiOH, 15-40 μm, 300 g, Mobile phase: 97% DCM, 3% MeOH, 0.1%NH₄OH). The fractions containing the product were collected andevaporated to dryness. The residue (0.43 g) was crystallized from amixture of MeOH and Et₂O. The precipitate was filtered off and driedyielding 0.394 g (30%) of compound 18 (MP: 165° C. (DSC)).

Preparation of Compound 1

Compound 1 was prepared according to an analogous procedure as describedfor the synthesis of compound 18, using intermediate 3 as startingmaterial (yield: 34%; MP: 169° C. (DSC)).

Preparation of Compound 5

Compound 5 was prepared according to an analogous procedure as describedfor the synthesis of compound 18, using intermediate 6 as startingmaterial (yield: 43%; MP: 251° C. (DSC)).

Preparation of Compound 6

Compound 6 was prepared according to an analogous procedure as describedfor the synthesis of compound 18, using intermediate 8 as startingmaterial (yield: 36%; MP: 183° C. (DSC)).

Preparation of Compound 7

Compound 7 was prepared according to an analogous procedure as describedfor the synthesis of compound 18, using intermediate 10 as startingmaterial (yield: 20%; MP: 171° C. (DSC)).

Preparation of Compound 8

Compound 8 was prepared according to an analogous procedure as describedfor the synthesis of compound 18, using intermediate 14 as startingmaterial (yield: 29%; MP: 185° C. (DSC)).

Preparation of Compound 10

Compound 10 was prepared according to an analogous procedure asdescribed for the synthesis of compound 18, using intermediate 17 asstarting material (yield: 55%; MP: 223° C. (DSC)).

Preparation of Compound 16

Compound 16 was prepared according to an analogous procedure asdescribed for the synthesis of compound 18, using intermediate 20 asstarting material (yield: 43%; MP: 164° C. (DSC)).

Preparation of Compound 25

A solution of tetrabutylammonium fluoride 1M in THF (0.536 mL; 0.536mmol) was added at 5° C. to a solution of intermediate 29 (181 mg; 0.268mmol) in THF and the reaction mixture was stirred at room temperaturefor 3 hours. The reaction mixture was diluted with DCM and a 10% aqueoussolution of K₂CO₃ was added. The organic layer was filtered throughChromabond® and evaporated to dryness. The residue was purified bychromatography over silica gel (irregular SiOH, 10 g; mobile phase:gradient from 0.2% NH₄OH, 2% MeOH, 98% DCM to 0.4% NH₄OH, 4% MeOH, 96%DCM). The fractions containing the product were collected and evaporatedto dryness yielding 148 mg (98%) of compound 25.

Preparation of Compound 26

Compound 26 was prepared according to an analogous procedure asdescribed for the synthesis of compound 25, using intermediate 30 asstarting material (yield: 100%).

Preparation of Compound 56

Compound 56 was prepared according to an analogous procedure asdescribed for the synthesis of compound 25, using intermediate 48 asstarting material (yield: 89%).

Preparation of Compound 29

Compound 29 was prepared according to an analogous procedure asdescribed for the synthesis of compound 25, using intermediate 35 asstarting material (yield: 28%; MP: 112° C. (Kofler)).

Preparation of Compound 30

Compound 30 was prepared according to an analogous procedure asdescribed for the synthesis of compound 25, using intermediate 36 asstarting material (yield: 39%; MP: 186° C. (Kofler)).

Preparation of Compound 31

Compound 31 was prepared according to an analogous procedure asdescribed for the synthesis of compound 25, using intermediate 37 asstarting material (yield: 54%; MP: 168° C. (Kofler)).

Preparation of Compound 37

Compound 37 was prepared according to an analogous procedure asdescribed for the synthesis of compound 25, using intermediate 45 asstarting material (yield: 37%; MP: 198° C. (Kofler)).

Preparation of Compound 38

Compound 38 was prepared according to an analogous procedure asdescribed for the synthesis of compound 25, using intermediate 46 asstarting material (yield: 17%; MP: 209° C. (Kofler)).

Preparation of Compound 39

Compound 39 was prepared according to an analogous procedure asdescribed for the synthesis of compound 25, using intermediate 47 asstarting material (yield: 18%; MP: 177° C. (Kofler)).

Preparation of Compound 63

Compound 63 was prepared according to an analogous procedure asdescribed for the synthesis of compound 25, using intermediate 61 asstarting material.

Purification by silica gel chromatography (Spherical bare silica 5 μm150×30.0 mm, Mobile phase: Gradient from 0.2% NH₄OH, 98% DCM, 2% MeOH to0.8% NH₄OH, 92% DCM, 8% MeOH). The pure fractions were collected and thesolvent was evaporated yielding 171 mg of a fraction A. Fraction A waspurified by achiral SFC (Stationary phase: CYANO 6 μm 150×21.2 mm,Mobile phase: 70% CO₂, 30% MeOH (0.3% iPrNH₂). The fractions containingthe product were collected and the solvent was evaporated to give 124 mgof a fraction B. 18 mg of this fraction B were washed with water. DCMwas added and the mixture was filtered over a phase separator filter.The solvent was evaporated to give 8 mg of compound 63 (white; MP: 191°C. (Kofler)).

Preparation of Compound 64

Compound 64 was prepared according to an analogous procedure asdescribed for the synthesis of compound 25, using intermediate 62 asstarting material (yield: 88%; MP: 204° C. (Kofler)).

Preparation of Compound 74

Compound 74 was prepared according to an analogous procedure asdescribed for the synthesis of compound 25, using intermediate 71 asstarting material (yield: 55%; MP: 200° C. (Kofler)).

Preparation of Compound 76

Compound 76 was prepared according to an analogous procedure asdescribed for the synthesis of compound 25, using intermediate 73 asstarting material (yield: 86%; MP: 178° C. (Kofler)).

Example B2 Preparation of Compound 19

A mixture of intermediate 24 (0.37 g; 0.7 mmol) and isopropylamine (1.8mL; 20.5 mmol) in acetonitrile (10 mL) was heated at 100° C. overnightin an autoclave. The solution was poured onto cooled water and theproduct was extracted with EtOAc. The organic layer was dried overMgSO₄, filtered and evaporated to dryness. The residue (0.68 g) waspurified by chromatography over silica gel (Spherical silica, 5 μm,150*30.0 mm, Mobile phase: Gradient from 0.2% NH₄OH, 98% DCM, 2% MeOH to0.8% NH₄OH, 92% DCM, 8% MeOH). The fractions containing the product werecollected and evaporated to dryness. The residue (0.26 g) wascrystallized from a mixture of MeOH and Et₂O. The precipitate wasfiltered off and dried yielding 0.190 g (56%) of compound 19 (MP: 162°C. (DSC)).

Preparation of Compound 2

Compound 2 was prepared according to an analogous procedure as describedfor the synthesis of compound 19, using intermediate 4 as startingmaterial (yield: 33%; MP: 124° C. (DSC)).

Preparation of Compound 9

Compound 9 was prepared according to an analogous procedure as describedfor the synthesis of compound 19, using intermediate 15 as startingmaterial (yield: 28%; MP: 142° C. (DSC)).

Preparation of Compound 11

Compound 11 was prepared according to an analogous procedure asdescribed for the synthesis of compound 19, using intermediate 18 asstarting material (yield: 42%; MP: 195° C. (DSC)).

Preparation of Compound 17

Compound 17 was prepared according to an analogous procedure asdescribed for the synthesis of compound 19, using intermediate 21 asstarting material (yield: 64%; MP: 132° C. (DSC)).

Preparation of Compound 32

Compound 32 was prepared according to an analogous procedure asdescribed for the synthesis of compound 19, using intermediate 38 asstarting material (yield: 64%; MP: 124° C. (Kofler)).

Preparation of Compound 33

Compound 33 was prepared according to an analogous procedure asdescribed for the synthesis of compound 19, using intermediate 39 asstarting material (yield: 44%; MP: 133° C. (Kofler)).

Preparation of Compound 34

Compound 34 was prepared according to an analogous procedure asdescribed for the synthesis of compound 19, using intermediate 40 asstarting material (yield: 16%; MP: 136° C. (Kofler)).

Example B3 Preparation of Compound 20

A mixture of intermediate 24 (0.79 g; 1.48 mmol) and methylamine (30 mLof a 2 M solution in THF; 59 mmol) was heated at 70° C. overnight in anautoclave. The solution was poured onto cooled water and the product wasextracted with EtOAc. The organic layer was dried over MgSO₄, filteredand evaporated to dryness. The residue (0.54 g) was purified bychromatography over silica gel (Irregular SiOH, 15-40 μm 30 g, Mobilephase: 0.1% NH₄OH, 95% DCM, 5% MeOH). The fractions containing theproduct were collected and evaporated to dryness. The residue (0.19 g)was crystallized from a mixture of ACN and Et₂O. The precipitate wasfiltered and dried yielding 0.094 g (14%) of compound 20 (MP: 141° C.(DSC)).

Preparation of Compound 57

A mixture of intermediate 52 (194 mg; 0.304 mmol), methylamine (6 mL ofa 2 M solution in THF; 12 mmol) was heated at 70° C. for 18 hours in asealed tube. The reaction mixture was evaporated to dryness.Trifluoroacetic acid (0.5 mL; 6.534 mmol) was added dropwise at 5° C. toa solution of the residue in DCM (5 mL). The reaction mixture wasallowed to warm slowly to room temperature and stirred for 18 hours. Thereaction mixture was diluted with DCM and a 10% aqueous solution ofK₂CO₃ was added. The organic layer was filtered through a phaseseparator filter and evaporated to dryness. The residue was purified bychromatography over silica gel (irregular SiOH, 40 g; mobile phase: 1%NH₄OH, 89% DCM, 10% MeOH). The fractions containing the product werecollected and evaporated to dryness. The residue was crystallized fromDIPE and the precipitate was filtered and dried yielding 48 mg (33%) ofcompound 57 (MP: gum 90° C. (Kofler))

Preparation of Compound 58

Compound 58 was prepared according to an analogous procedure asdescribed for the synthesis of compound 57, using intermediate 53 asstarting material (yield: 41%; MP: 176° C. (Kofler)).

Preparation of Compound 59

Compound 59 was prepared according to an analogous procedure asdescribed for the synthesis of compound 57, using intermediate 54 asstarting material (yield: 35%; MP: 139° C. (Kofler)).

Preparation of Compound 70

Compound 70 was prepared according to an analogous procedure asdescribed for the synthesis of compound 20, using intermediate 65 asstarting material (yield: 18%, MP=178° C. (kofler)).

Preparation of Compound 71

Compound 71 was prepared according to an analogous procedure asdescribed for the synthesis of compound 20, using intermediate 66 asstarting material (yield: 79%, MP: 135° C. (Kofler)).

Example B4 Preparation of Compound 21

Under N₂ at 10° C., sodium hydride (60% in mineral oil) (0.29 g; 7.3mmol) was added to a solution of intermediate 22 (1 g; 2.4 mmol) in DMF(8 mL). The solution was stirred at 10° C. for 30 minutes. Then, asolution of 2-(chloromethyl)-N,N-dimethyl-1H-imidazole-sulfonamide (1 g;4.9 mmol) in DMF (3 mL) was added drop wise and the reaction mixture wasallowed to warm to room temperature for 5 hours. The solution was pouredonto cooled water and the product was extracted with EtOAc. The organiclayer was washed by water and dried over MgSO₄, filtered and evaporatedto dryness yielding 1.8 g (quantitative) of compound 21.

Preparation of Compound 3

Compound 3 was prepared according to an analogous procedure as describedfor the synthesis of compound 21, using intermediate 2 as startingmaterial (yield: 15%).

Preparation of Compound 12

Compound 12 was prepared according to an analogous procedure asdescribed for the synthesis of compound 21, using intermediate 16 asstarting material (quantitative yield).

Preparation of Compound 14

Compound 14 was prepared according to an analogous procedure asdescribed for the synthesis of compound 21, using intermediate 19 asstarting material (quantitative yield).

Preparation of Compound 27

Under N₂ at −30° C., sodium hydride (60% in mineral oil) (125 mg; 3.121mmol) was added to a solution of intermediate 27 (500 mg; 1.04 mmol) inDMF (15 mL). The reaction mixture was stirred at −10° C. for 30 minutes.Then a solution of2-(chloromethyl)-N,N-dimethyl-1H-imidazole-sulfonamide (512 mg; 2.289mmol) in DMF (5 mL) was added dropwise. The reaction mixture was stirredbelow −10° C. for 1 hour, then 1 hour at 0° C. and was allowed to warmup to room temperature (1 hour more). The solution was poured ontoice/water and the product was extracted with EtOAc. The organic layerwas washed with brine, dried over MgSO₄, filtered and evaporated todryness. The residue was purified by chromatography over silica gel(irregular SiOH, 30 g, 30 μm; mobile phase: gradient from 100% DCM to0.2% NH₄OH, 2% MeOH, 98% DCM). The fractions containing the product werecollected and evaporated to dryness yielding 325 mg (47%) of compound27.

MP: gum, 100° C. (Kofler).

Preparation of Compound 28

Compound 28 was prepared according to an analogous procedure asdescribed for the synthesis of compound 27, using intermediate 28 asstarting material (yield: 73%; MP: gum, 90° C. (Kofler)).

Preparation of Compound 42

Compound 42 was prepared according to an analogous procedure asdescribed for the synthesis of compound 27, using intermediate 26 asstarting material (yield: 52%; MP: 168° C. (Kofler)).

Preparation of Compound 35

Compound 35 was prepared according to an analogous procedure asdescribed for the synthesis of compound 21, using intermediate 32 asstarting material (yield: 9%; MP: 128° C. (Kofler)).

Preparation of Compound 36

Compound 36 was prepared according to an analogous procedure asdescribed for the synthesis of compound 21, using intermediate 33 asstarting material (yield: 11%; MP: 108° C. (Kofler)).

Preparation of Compound 40

Compound 40 was prepared according to an analogous procedure asdescribed for the synthesis of compound 21, using intermediate 42 asstarting material (yield: 16%; MP: 139° C. (Kofler)).

Preparation of Compound 41

Compound 41 was prepared according to an analogous procedure asdescribed for the synthesis of compound 21, using intermediate 43 asstarting material (yield: 13%; MP: gum at 109° C. (Kofler)).

Preparation of Compound 67

Compound 67 was prepared according to an analogous procedure asdescribed for the synthesis of compound 27, using intermediate 59 asstarting material (yield: 11%; MP: 189° C. (kofler)).

Preparation of Compound 68

Compound 68 was prepared according to an analogous procedure asdescribed for the synthesis of compound 27, using intermediate 60 asstarting material.

Purification by chromatography over silica gel (Irregular SiOH 20-45 μm450 g, Mobile phase: 40% Heptane, 10% MeOH (+10% NH₄OH), 50% EtOAc) gave2 fractions of compound 68: 430 mg (26%, MP: 182° C. (kofler)) and 910mg (57%).

Example B5 Preparation of Compound 24

Intermediate 11 (0.2 g; 0.66 mmol), 3,5-dimethoxyphenyl boronic acid(0.18 g; 0.98 mmol), tricyclohexylphosphine (0.018 g; 0.065 mmol),palladium (II) acetate (47% Pd) (0.015 g; 0.065 mmol), and triethylamine(0.183 mL; 1.31 mmol) in toluene (10 mL) were stirred under carbonmonoxide (10 bar) at 100° C. for 18 hours in an autoclave. The solutionwas cooled, poured onto cooled water and EtOAc was added. The solutionwas filtered through a pad of Celite®. The filtrate was extracted withEtOAc and the organic layer was washed with water, dried over MgSO₄ andevaporated to dryness. The residue (344 g) was purified bychromatography over silica gel (Spherical silica, 5 μm, 150×30.0 mm,Mobile phase: Gradient from 71% Heptane, 1% MeOH (+10% NH₄OH), 28% EtOActo 0% heptane, 20% MeOH (+10% NH₄OH), 80% EtOAc). The fractionscontaining the product were collected and evaporated to dryness. Theresulting residue (56 mg) was crystallized from Et₂O. The precipitatewas filtered and dried affording 43 mg (17%) of compound 24 (MP: 194° C.(kofler)).

Preparation of Compound 23

Compound 23 was prepared according to an analogous procedure asdescribed for the synthesis of compound 24, using intermediate 11 and3-methoxyphenyl boronic acid as starting materials (yield: 11%).

Example B6 Preparation of Compound 46

Trifluoroacetic acid (34 μL; 4.445 mmol) was added dropwise at 5° C. toa solution of intermediate 29 (150 mg; 0.222 mmol) in DCM (5 mL). Thereaction mixture was allowed to warm slowly to room temperature andstirred for 48 hours. The reaction mixture was diluted with DCM and a10% aqueous solution of K₂CO₃ was added. The organic layer was filteredthrough a phase separator filter and evaporated to dryness. The residuewas purified by chromatography over silica gel (Spherical bare silica 5μm 150×30.0 mm; mobile phase: gradient from 0.4% NH₄OH, 96% DCM, 4% MeOHto 1.7% NH₄OH, 83% DCM, 17% MeOH). The fractions containing the productwere collected and evaporated to dryness yielding 40 mg of compound 46(39%; MP: 186° C. (Kofler)).

Preparation of Compound 47

Compound 47 was prepared according to an analogous procedure asdescribed for the synthesis of compound 46, using intermediate 48 asstarting material (yield: 14%; MP: 165° C. (Kofler)).

Preparation of Compound 48

Compound 48 was prepared according to an analogous procedure asdescribed for the synthesis of compound 46, using intermediate 30 asstarting material (yield: 53%; MP: 173° C. (Kofler)).

Example B7 Preparation of Compound 50

Compound 50 was prepared according to an analogous procedure asdescribed for the synthesis of compound 25, using intermediate 49 asstarting material (yield: 81%).

Preparation of Compound 51

Compound 51 was prepared according to an analogous procedure asdescribed for the synthesis of compound 25, using intermediate 50 asstarting material (yield: 100%).

Preparation of Compound 52

Compound 52 was prepared according to an analogous procedure asdescribed for the synthesis of compound 25, using intermediate 51 asstarting material (yield: 100%).

Preparation of Compound 65

Compound 65 was prepared according to an analogous procedure asdescribed for the synthesis of compound 25, using intermediate 63 asstarting material (yield: 47%, MP: 164° C. (Kofler)).

Preparation of Compound 66

Compound 66 was prepared according to an analogous procedure asdescribed for the synthesis of compound 25, using intermediate 64 asstarting material (yield: 68%). Purification by chromatography oversilica gel (irregular SiOH 15-40 μm 300 g MERCK, Mobile phase: 43%Heptane, 7% MeOH (+10% NH₄OH), 50% EtOAc) gave 2 fractions of compound66: 228 mg (39%; MP: 178° C. (Kofler) and 162 mg (28%).

Example B8 Preparation of Compound 53

Compound 53 was prepared according to an analogous procedure asdescribed for the synthesis of compound 46, using intermediate 49 asstarting material (yield: 36%, MP: 184° C. (Kofler)).

Preparation of Compound 54

Compound 54 was prepared according to an analogous procedure asdescribed for the synthesis of compound 46, using intermediate 50 asstarting material (yield: 53%, MP: 167° C. (Kofler)).

Preparation of Compound 55

Compound 55 was prepared according to an analogous procedure asdescribed for the synthesis of compound 46, using intermediate 51 asstarting material (yield: 34%, MP: 167° C. (Kofler)).

Example B9 Preparation of Compound 60

A mixture of intermediate 55 (150 mg; 0.23 mmol) and isopropylamine (0.6mL; 6.9 mmol) in acetonitrile (6 mL) was heated at 100° C. for 2 hoursin a sealed tube. The reaction mixture was evaporated to dryness.Trifluoroacetic acid (1 mL; 13.07 mmol) was added dropwise at 5° C. to asolution of the previous residue (140 mg) in DCM (10 mL). The reactionmixture was allowed to warm slowly to room temperature and stirred for18 hours. The reaction mixture was diluted with DCM and a 10% aqueoussolution of K₂CO₃ was added. The organic layer was filtered through aphase separator filter and evaporated to dryness. The residue waspurified by chromatography over silica gel (irregular SiOH, 40 g; mobilephase: 1% NH₄OH, 89% DCM, 10% MeOH). The fractions containing theproduct were collected and evaporated to dryness. The residue (87 mg;73%) was crystallized from ACN and the precipitate was filtered anddried yielding 22 mg (18%) of compound 60 (MP: 126° C. (Kofler)).

Preparation of Compound 61

 and Compound 61′

Compound 61 was prepared according to an analogous procedure asdescribed for the synthesis of compound 60, using intermediate 56 asstarting material (yield: 41%). Compound 61 (97 mg; 0.19 mmol) wasdissolved in ACN and fumaric acid (23 mg; 0.195 mmol) was added. Theproduct was crystallized from ACN. The precipitate was filtered anddried yielding 104 mg (36%) of compound 61′ (MP: 140° C. (gum, Kofler)).

Preparation of Compound 62

 and Compound 62′

Compound 62 was prepared according to an analogous procedure asdescribed for the synthesis of compound 60, using intermediate 57 asstarting material (yield: 63%). Compound 62 (170 mg; 0.35 mmol) wasdissolved in ACN and fumaric acid (41 mg; 0.354 mmol) was added. Theproduct was crystallized from ACN/EtOH. The precipitate was filtered anddried yielding 180 mg (54%) of compound 62′ (MP: 255° C. (Kofler)).

Preparation of Compound 72

Compound 72 was prepared according to an analogous procedure asdescribed for the synthesis of compound 19, using intermediate 67 asstarting material (yield: 40%; MP: gum, 80° C. (Kofler)).

Preparation of Compound 73

 and Compound 73′

Compound 73 was prepared according to an analogous procedure asdescribed for the synthesis of compound 19, using intermediate 68 asstarting material (yield: 75%). Fumaric acid (41 mg; 0.35 mmol) wasadded to a solution of compound 73 (171 mg; 0.35 mmol) in acetone (1mL). The mixture was stirred at rt for 2 hours. The precipitate wasfiltered, washed with few acetone and dried to give 186 mg (48%) ofcompound 73′ (MP: 240° C. (Kofler)).

Conversion C1:

Preparation of Compound 22

A mixture of compound 21 (1.45 g; 2 mmol) in HCl 6 N (2.8 mL) anddioxane (10 mL) was heated at 100° C. for 2 hours. The solution wascooled down to room temperature, poured onto cooled water, basified withNH₄OH and the product was extracted with EtOAc. The organic layer wasdried over MgSO₄, filtered and evaporated to dryness. The residue (1.22g) was purified by chromatography over silica gel (Irregular SiOH, 15-40μm, 40 g, Mobile phase: 96% DCM, 4% MeOH, 0.1% NH₄OH). The fractionscontaining the product were collected and evaporated to dryness. Theresidue (0.6 g) was purified again by chromatography (Irregular SiOH,15-40 μm, 40 g, Mobile phase: 95% DCM, 5% MeOH, 0.5% NH₄OH). Thefractions containing the product were collected and evaporated todryness. The resulting residue (0.4 g) purified by achiral SFC(Stationary phase: 2-ethylpyridine, 6 μm 150×21.2 mm), Mobile phase: 80%CO₂, 20% MeOH (0.3% iPrNH₂)). The fractions containing the product werecollected and evaporated to dryness. The residue (0.206 g) wascrystallized from a mixture of ACN and Et₂O. the precipitate wasfiltered and dried yielding 0.17 g (17%) of compound 22 (MP: 231° C.(DSC)).

Preparation of Compound 4

Compound 4 was prepared according to an analogous procedure as describedfor the synthesis of compound 22, using compound 3 as starting material(yield: 46%).

Preparation of Compound 13

Compound 13 was prepared according to an analogous procedure asdescribed for the synthesis of compound 22, using compound 12 asstarting material (yield: 20%).

Preparation of Compound 15

Compound 15 was prepared according to an analogous procedure asdescribed for the synthesis of compound 22, using compound 14 asstarting material (yield: 22%) MP: 212° C. (DSC)).

Preparation of Compound 43

Compound 43 was prepared according to an analogous procedure asdescribed for the synthesis of compound 22, using compound 42 asstarting material (yield: 38%, MP: 223° C. (Kofler)).

Preparation of Compound 44

Compound 44 was prepared according to an analogous procedure asdescribed for the synthesis of compound 22, using compound 27 asstarting material (yield: 42%, MP: 220° C. (Kofler)).

Preparation of Compound 45

Compound 45 was prepared according to an analogous procedure asdescribed for the synthesis of compound 22, using compound 28 asstarting material (yield: 59%, MP: 260° C. (Kofler)).

Preparation of Compound 69

Compound 69 was prepared according to an analogous procedure asdescribed for the synthesis of compound 22, using compound 68 asstarting material (yield: 82%, MP: 260° C. (Kofler)).

Preparation of Compound 75

Compound 75 was prepared according to an analogous procedure asdescribed for the synthesis of compound 22, using compound 67 asstarting material (yield: 37%, MP: >260° C. (Kofler)).

Conversion C2:

Preparation of Compound 49

A mixture of compound 24 and (triphenylphosphoranylidene)acetonitrile intoluene was refluxed all over the week end. The reaction mixture wascooled to room temperature, poured onto a 10% aqueous solution of K₂CO₃and extracted with EtOAc/MeOH. The organic layer was decanted, driedover MgSO₄, filtered and evaporated to dryness. The residue was purifiedby chromatography over silica gel (irregular SiOH, 15-40 μm, 40 g;mobile phase: 42% Heptane, 8% MeOH (+10% NH₄OH), 50% EtOAc). Thefractions containing the product were collected and evaporated todryness yielding an intermediate residue (22 mg) which was taken up withEt₂O. The precipitate was filtered and dried yielding 16 mg of compound49 (8%, MP: 217° C. (Kofler)).

Analytical Part

LCMS (Liquid Chromatography/Mass Spectrometry)

The LC measurement was performed using a UPLC (Ultra Performance LiquidChromatography) Acquity (Waters) system comprising a binary pump withdegasser, an autosampler, a diode-array detector (DAD) and a column asspecified in the respective methods below, the column is hold at atemperature of 40° C. Flow from the column was brought to a MS detector.The MS detector was configured with an electrospray ionization source.The capillary needle voltage was 3 kV and the source temperature wasmaintained at 130° C. on the Quattro (triple quadrupole massspectrometer from Waters). Nitrogen was used as the nebulizer gas. Dataacquisition was performed with a Waters-Micromass MassLynx-Openlynx datasystem.

Reversed phase UPLC was carried out on a Waters Acquity BEH (bridgedethylsiloxane/silica hybrid) C18 column (1.7 μm, 2.1×100 mm) with a flowrate of 0.343 ml/min. Two mobile phases (mobile phase A: 95% 7 mMammonium acetate/5% acetonitrile; mobile phase B: 100% acetonitrile)were employed to run a gradient condition from 84.2% A and 15.8% B (holdfor 0.49 minutes) to 10.5% A and 89.5% B in 2.18 minutes, hold for 1.94min and back to the initial conditions in 0.73 min, hold for 0.73minutes. An injection volume of 2 μl was used. Cone voltage was 20V forpositive and negative ionization mode. Mass spectra were acquired byscanning from 100 to 1000 in 0.2 seconds using an interscan delay of 0.1seconds.

Melting Points

For a number of compounds, melting points (MP) were determined with aDSC1 (Mettler-Toledo). Melting points were measured with a temperaturegradient of 10° C./minute. Maximum temperature was 350° C. Values arepeak values.”

For a number of compounds, melting points were obtained with a Koflerhot bench, consisting of a heated plate with linear temperaturegradient, a sliding pointer and a temperature scale in degrees Celsius.

NMR

The NMR experiments were carried out using a Bruker Avance 500 III usinginternal deuterium lock and equipped with reverse triple-resonance (¹H,¹³C, ¹⁵N TXI) probe head. Chemical shifts (δ) are reported in parts permillion (ppm).

TABLE Co. No. means compound number; Retention time (R_(t)) in minutes;MP means melting point (° C.); dec means decomposition; n.d. means notdetermined. Co. (Kofler (K) No. Compound MP or DSC) R_(t) [M + H]⁺ 1

  169 DSC 2.61 454 2

  124 DSC 2.52 495 3

n.d. — n.d. n.d. 4

n.d. — 2.50 490 5

  251 DSC 2.71 486 6

  183 DSC 2.62 436 7

  171 DSC 2.66 418 8

  185 DSC 2.28 422 9

  142 DSC 2.14 463 10

  223 DSC 2.33 490 11

  195 DSC 2.24 n.d. 12

n.d. — n.d. n.d. 13

dec K 2.24 526 14

n.d. — n.d. n.d. 15

  212 DSC 2.17 476 16

  164 DSC 2.24 440 17

  132 DSC 2.13 481 18

  165 DSC 2.22 458 19

  162 DSC 2.12 499 20

  141 DSC 1.95 471 21

n.d. — n.d. n.d. 22

  231 DSC 2.14 494 23

n.d. — 2.47 361 24

  194 K 2.53 391 25

n.d. — n.d. n.d. 26

n.d. — n.d. n.d. 27

  100 (gum) K 3.14 668 28

  90  (gum) K 3.09 686 29

  112 K 2.24 455 30

  186 K 2.26 437 31

  168 K 2.32 419 32

  124 K 2.14 493 33

  133 K 2.14 478 34

  136 K 2.14 460 35

  128 K 2.53 598 36

  108 K 2.61 580 37

  198 K 2.23 455 38

  209 K 2.26 437 39

  177 K 2.29 419 40

  139 K 2.53 598 41

  109 (gum) K 2.60 580 42

  168 K 3.02 704 43

  223 K 1.89 497 44

  220 K 1.95 461 45

  260 K 1.94 479 46

  186 K 1.91 461 47

  165 K 1.96 425 48

  173 K 1.94 443 49

  217 K 2.59 414 50

n.d. — n.d. n.d. 51

n.d. — n.d. n.d. 52

n.d. — n.d. n.d. 53

  184 K 1.97 475 54

  167 K 2.00 457 55

  167 K 2.03 439 56

n.d. — n.d. n.d. 57

  90  (gum) K 1.93 474 58

  176 K 2.19 456 59

  139 K 2.13 438 60

  126 K 2.14 516 61

n.d. — n.d. n.d. 61′

  140 (gum) K 2.16 498

62

n.d. — n.d. n.d. 62′

  255 (gum) K 2.40 480

63

  191 K 2.30 444 64

  204 K 2.34 426 65

  164 K 2.36 458 66

  178 K 2.4 440 67

  189 K 2.67 587 68

  182 K 2.7 569 69

  260 K 2.26 462 70

  178 K 2.03 457 71

  135 K 2.05 439 72

  80  (gum) K 2.18 499 73

n.d. — 2.20 481 73′

  240 K 2.22 481

74

  200 K 2.20 438 75

>260 K 2.24 480 76

  178 K 2.18 456

Compound 19

¹H NMR (500 MHz, DMSO-d₆) δ 8.24 (s, 1H), 8.20 (s, 1H), 7.81 (s, 1H),7.59 (d, J=9.1 Hz, 1H), 7.26 (d, J=2.8 Hz, 1H), 7.20 (dd, J=2.8, 9.1 Hz,1H), 7.07 (t, J=8.0 Hz, 1H), 3.91 (s, 6H), 3.89 (s, 3H), 3.73 (t, J=7.2Hz, 2H), 2.73 (t, J=7.2 Hz, 2H), 2.69-2.62 (m, 1H), 1.58 (br. s., 1H),0.92 (d, J=6.0 Hz, 6H)

Compound 20

¹H NMR (500 MHz, DMSO-d₆) δ 8.24 (s, 1H), 8.20 (s, 1H), 7.81 (s, 1H),7.59 (d, J=8.8 Hz, 1H), 7.26 (d, J=2.8 Hz, 1H), 7.21 (dd, J=2.8, 8.8 Hz,1H), 7.08 (t, J=8.2 Hz, 1H), 3.92 (s, 6H), 3.89 (s, 3H), 3.75 (t, J=7.2Hz, 2H), 2.71 (t, J=7.2 Hz, 2H), 2.34-2.21 (m, 4H)

Compound 22

¹H NMR (500 MHz, DMSO-d₆) δ 11.87 (br. s., 1H), 8.25 (s, 1H), 8.20 (s,1H), 7.81 (s, 1H), 7.60 (d, J=8.8 Hz, 1H), 7.51 (dd, J=2.8, 8.8 Hz, 1H),7.44 (d, J=2.8 Hz, 1H), 7.04 (t, J=8.0 Hz, 1H), 7.00 (s, 1H), 6.81 (s,1H), 4.85 (s, 2H), 3.89 (s, 9H)

Pharmacological Part

Biological Assays A

FGFR1 (Enzymatic Assay)

In a final reaction volume of 30 μL, FGFR1 (h) (25 ng/ml) was incubatedwith 50 mM HEPES pH 7.5, 6 mM MnCl₂, 1 mM DTT, 0.1 mM Na₃VO₄, 0.01%Triton-X-100, 500 nM Btn-Flt3 and 5 μM ATP in the presence of compound(1% DMSO final). After incubation for 60 minutes at room temperature thereaction was stopped with 2.27 nM EU-anti P-Tyr, 7 mM EDTA, 31.25 nMSA-XL-665 and 0.02% BSA which was present for 60 minutes at roomtemperature. Time-Resolved Fluorescence Resonance Energy Transfer(TR-FRET) signal (ex340 nm. Em 620 nm, em 655 nm) was measuredafterwards and results are expressed in RFU (Relative FluorescenceUnits). In this assay, the inhibitory effect of different compoundconcentrations (range 10 μM to 0.1 nM) was determined and used tocalculate an IC₅₀ (M) and pIC₅₀ (−log IC₅₀) value.

FGFR2 (Enzymatic Assay)

In a final reaction volume of 30 μL, FGFR2 (h) (150 ng/ml) was incubatedwith 50 mM HEPES pH 7.5, 6 mM MnCl₂, 1 mM DTT, 0.1 mM Na₃VO₄, 0.01%Triton-X-100, 500 nM Btn-Flt3 and 0.4 μM ATP in the presence of compound(1% DMSO final). After incubation for 60 minutes at room temperature thereaction was stopped with 2.27 nM EU-anti P-Tyr, 7 mM EDTA, 31.25 nMSA-XL-665 and 0.02% BSA which was present for 60 minutes at roomtemperature. Time-Resolved Fluorescence Resonance Energy Transfer(TR-FRET) signal (ex340 nm. Em 620 nm, em 655 nm) was measuredafterwards and results are expressed in (Relative Fluorescence Units).In this assay, the inhibitory effect of different compoundconcentrations (range 10 μM to 0.1 nM) was determined and used tocalculate an IC₅₀ (M) and pIC₅₀ (−log IC₅₀) value.

FGFR3 (Enzymatic Assay)

In a final reaction volume of 30 μL, FGFR3 (h) (40 ng/ml) was incubatedwith 50 mM HEPES pH 7.5, 6 mM MnCl₂, 1 mM DTT, 0.1 mM Na₃VO₄, 0.01%Triton-X-100, 500 nM Btn-Flt3 and 25 μM ATP in the presence of compound(1% DMSO final). After incubation for 60 minutes at room temperature thereaction was stopped with 2.27 nM EU-anti P-Tyr, 7 mM EDTA, 31.25 nMSA-XL-665 and 0.02% BSA which was present for 60 minutes at roomtemperature. Time-Resolved Fluorescence Resonance Energy Transfer(TR-FRET) signal (ex340 nm. Em 620 nm, em 655 nm) was measuredafterwards and results are expressed in RFU (Relative FluorescenceUnits). In this assay, the inhibitory effect of different compoundconcentrations (range 10 μM to 0.1 nM) was determined and used tocalculate an IC₅₀ (M) and pIC₅₀ (−log IC₅₀) value.

FGFR4 (Enzymatic Assay)

In a final reaction volume of 30 μL, FGFR4 (h) (60 ng/ml) was incubatedwith 50 mM HEPES pH 7.5, 6 mM MnCl₂, 1 mM DTT, 0.1 mM Na₃VO₄, 0.01%Triton-X-100, 500 nM Btn-Flt3 and 5 μM ATP in the presence of compound(1% DMSO final). After incubation for 60 minutes at room temperature thereaction was stopped with 2.27 nM EU-anti P-Tyr, 7 mM EDTA, 31.25 nMSA-XL-665 and 0.02% BSA which was present for 60 minutes at roomtemperature. Time-Resolved Fluorescence Resonance Energy Transfer(TR-FRET) signal (ex340 nm. Em 620 nm, em 655 nm) was measuredafterwards and results are expressed in RFU (Relative FluorescenceUnits). In this assay, the inhibitory effect of different compoundconcentrations (range 10 μM to 0.1 nM) was determined and used tocalculate an IC₅₀ (M) and pIC₅₀ (−log IC₅₀) value.

KDR (VEGFR2) (Enzymatic Assay)

In a final reaction volume of 30 μL, KDR (h) (150 ng/ml) was incubatedwith 50 mM HEPES pH 7.5, 6 mM MnCl₂, 1 mM DTT, 0.1 mM Na₃VO₄, 0.01%Triton-X-100, 500 nM Btn-Flt3 and 3 μM ATP in the presence of compound(1% DMSO final). After incubation for 120 minutes at room temperaturethe reaction was stopped with 2.27 nM EU-anti P-Tyr, 7 mM EDTA, 31.25 nMSA-XL-665 and 0.02% BSA which was present for 60 minutes at roomtemperature. Time-Resolved Fluorescence Resonance Energy Transfer(TR-FRET) signal (ex340 nm. Em 620 nm, em 655 nm) was measuredafterwards and results are expressed in RFU (Relative FluorescenceUnits). In this assay, the inhibitory effect of different compoundconcentrations (range 10 μM to 0.1 nM) was determined and used tocalculate an IC₅₀ (M) and pIC₅₀ (−log IC₅₀) value.

Ba/F3-FGFR1 (Minus IL3 or Plus IL3) (Cellular Proliferation Assay)

In a 384 well plate, 100 nl of compound dilution in DMSO was sprayedbefore adding 50 μl cell culture medium (phenol red free RPMI-1640, 10%FBS, 2 mM L-Glutamine and 50 μg/ml Gentamycin) containing 20000 cellsper well of Ba/F3-FGFR1-transfected cells. Cells were put in anincubator at 37° C. and 5% CO₂. After 24 hours, 10 μl of Alamar Bluesolution (0.5 mM K₃Fe(CN)₆, 0.5 mM K₄Fe(CN)₆, 0.15 mM Resazurin and 100mM Phosphate Buffer) was added to the wells, incubated for 4 hours at37° C. and 5% CO₂ before RFU's (Relative Fluorescence Units) (ex. 540nm., em. 590 nm.) were measured in a fluorescence plate reader.

In this assay, the inhibitory effect of different compoundconcentrations (range 10 μM to 0.1 nM) was determined and used tocalculate an IC₅₀ (M) and pIC₅₀ (−log IC₅₀) value. As a counterscreenthe same experiment was performed in the presence of 10 ng/ml murineIL3.

Ba/F3-FGFR3 (Minus IL3 or Plus IL3) (Cellular Proliferation Assay)

In a 384 well plate, 100 nl of compound dilution in DMSO was sprayedbefore adding 50 μl cell culture medium (phenol red free RPMI-1640, 10%FBS, 2 mM L-Glutamine and 50 μg/ml Gentamycin) containing 20000 cellsper well of Ba/F3-FGFR3-transfected cells. Cells were put in anincubator at 37° C. and 5% CO₂. After 24 hours, 10 μl of Alamar Bluesolution (0.5 mM K₃Fe(CN)₆, 0.5 mM K₄Fe(CN)₆, 0.15 mM Resazurin and 100mM Phosphate Buffer) was added to the wells, incubated for 4 hours at37° C. and 5% CO₂ before RFU's (Relative Fluorescence Units) (ex. 540nm., em. 590 nm.) were measured in a fluorescence plate reader.

In this assay, the inhibitory effect of different compoundconcentrations (range 10 μM to 0.1 nM) was determined and used tocalculate an IC₅₀ (M) and pIC₅₀ (−log IC₅₀) value. As a counterscreenthe same experiment was performed in the presence of 10 ng/ml murineIL3.

Ba/F3-KDR (Minus IL3 or Plus IL3) (Cellular Proliferation Assay)

In a 384 well plate, 100 nl of compound dilution in DMSO was sprayedbefore adding 50 μl cell culture medium (phenol red free RPMI-1640, 10%FBS, 2 mM L-Glutamine and 50 μg/ml Gentamycin) containing 20000 cellsper well of Ba/F3-KDR-transfected cells. Cells were put in an incubatorat 37° C. and 5% CO₂. After 24 hours, 10 μl of Alamar Blue solution (0.5mM K₃Fe(CN)₆, 0.5 mM K₄Fe(CN)₆, 0.15 mM Resazurin and 100 mM PhosphateBuffer) was added to the wells, incubated for 4 hours at 37° C. and 5%CO₂ before RFU's (Relative Fluorescence Units) (ex. 540 nm., em. 590nm.) were measured in a fluorescence plate reader.

In this assay, the inhibitory effect of different compoundconcentrations (range 10 μM to 0.1 nM) was determined and used tocalculate an IC₅₀ (M) and pIC₅₀ (−log IC₅₀) value. As a counterscreenthe same experiment was performed in the presence of 10 ng/ml murineIL3.

Ba/F3-FGFR4 (Cellular Proliferation Assay)

In a 384 well plate, 100 nl of compound dilution in DMSO was sprayedbefore adding 50 μl cell culture medium (phenol red free RPMI-1640, 10%FBS, 2 mM L-Glutamine and 50 μg/ml Gentamycin) containing 20000 cellsper well of Ba/F3-FGFR4-transfected cells. Cells were put in anincubator at 37° C. and 5% CO2. After 24 hours, 10 μl of Alamar Bluesolution (0.5 mM K₃Fe(CN)₆, 0.5 mM K₄Fe(CN)₆, 0.15 mM Resazurin and 100mM Phosphate Buffer) was added to the wells, incubated for 4 hours at37° C. and 5% CO₂ before RFU's (Relative Fluorescence Units) (ex. 540nm., em. 590 nm.) were measured in a fluorescence plate reader.

In this assay, the inhibitory effect of different compoundconcentrations (range 10 μM to 0.1 nM) was determined and used tocalculate an IC₅₀ (M) and pIC₅₀ (−log IC₅₀) value.

Data for the compounds of the invention in the above assays are providedin Table A1 (n.d. means not determined)

TABLE A1 BAF3- BAF3- BAF3- BAF3- BAF3- BAF3- VEGFR FGFR1 FGFR1 FGFR3FGFR3 KDR KDR BAF3- Comp. FGFR 1 FGFR 2 FGFR3 FGFR 4 KDR (MIN IL3 (PLUSIL3 (MIN IL3 (PLUS IL3 (MIN IL3 (PLUS IL3 FGFR4 No. pIC50 pIC50 pIC50pIC50 pIC50 pIC50) pIC50) pIC50) pIC50) pIC50) pIC50) (pIC50) 4 7.8 7.98.1 7.6 <6 6.1 <5 6.2 <5 <5 <5 5.4 24 <6 6.1 6.1 <6 <6 <5 <5 <5 <5 <5 <5<5 23 <6 <6 <6 <6 <6 <5 <5 <5 <5 <5 <5 <5 20 8.0 7.9 7.9 7.6 6.8 7.6 <57.6 <5 6.0 <5 6.7 17 8.1 8.0 7.8 7.5 6.9 7.6 <5 7.7 <5 5.5 <5 6.8 15 8.38.3 8.6 8.1 6.4 6.7 <5 ~7.15 <5 <5 <5 5.8 13 7.8 7.8 7.9 6.9 6.6 5.5 <55.9 <5 5.1 <5 5.2 22 8.4 8.3 8.5 8.3 6.9 6.8 <5 7.4 <5 5.3 <5 6.7 2 8.27.6 7.6 7.4 6.6 7.7 <5 7.6 <5 5.7 <5 6.3 19 8.3 7.8 7.8 7.7 6.9 8.8 <58.6 <5 6.2 <5 8.2 6 7.1 7.3 7.4 6.5 <6 5.5 <5 5.5 <5 <5 <5 5.0 11 7.97.2 7.4 6.8 6.3 7.4 <5 7.3 <5 5.4 <5 6.3 7 6.2 6.4 6.5 5.4 <6 <5 <5 <5<5 <5 <5 <5 9 8.3 8.2 8.0 7.3 6.3 7.2 <5 ~7.09 <5 5.2 <5 6.2 5 7.2 7.47.6 6.3 ~6 5.5 <5 5.3 <5 <5 <5 <5 16 7.9 8.3 8.6 7.6 6.7 6.3 <5 6.4 <55.2 <5 5.7 18 8.8 8.6 8.8 8.3 7.4 7.2 <5 ~7.68 <5 5.6 <5 6.6 10 7.9 7.88.1 6.7 6.3 6.2 <5 6.3 <5 ~5 <5 5.1 1 8.0 8.2 8.2 7.4 6.6 6.0 <5 6.4 <5~5 <5 5.6 8 7.3 7.6 7.7 6.8 6.1 5.4 <5 5.6 <5 <5 <5 5.2

Biological Assays B

Enzyme Binding Assays (KINOMEscan®)

Kinase enzyme binding affinities of compounds disclosed herein weredetermined using the KINOMEscan® technology performed by DiscoveRxCorporation, San Diego, Calif., USA (www.kinomescan.com). Table B1reports the obtained pKd values (−log Kd; Kd (M) is inhibitor bindingconstant):

TABLE B1 Compound FGFR1_pKd FGFR2_pKd FGFR3_pKd FGFR4_pKd VEGFR2_pKd 767.2 7.8 7.5 6.7 <5.5 75 7.4 8.0 7.8 6.7 <5.5 67 6.5 6.6 6.1 <5.5 <5.5 707.5 7.4 7.1 7.0 <5.5 69 6.8 7.3 6.8 6.0 <5.5 43 7.8 8.1 7.7 7.3 <5.5 457.1 7.5 7.1 6.3 <5.5 44 6.4 6.8 6.4 <5.5 <5.5 60 8.2 8.3 7.9 7.4 6.0 61′ 7.3 7.7 7.2 6.7 <5.5 63 6.4 7.2 6.9 5.8 <5.5 68 5.9 6.0 <5.5 <5.5<5.5 71 6.2 6.4 5.9 <5.5 <5.5 59 6.0 <5.5 <5.5 <5.5 <5.5 58 6.5 6.4 6.25.7 <5.5 57 7.5 7.4 7.2 6.8 5.7  73′ 6.9 7.2 6.7 5.9 5.5 73 7.2 7.3 6.85.9 <5.5 64 6.2 6.4 6.0 <5.5 <5.5 72 8.1 8.0 7.8 7.3 5.6 74 6.1 6.9 6.45.7 <5.5 66 5.9 6.3 5.9 <5.5 <5.5 53 7.3 7.5 7.2 6.7 <5.5 54 6.1 6.5 6.2<5.5 <5.5 55 <5.5 5.6 5.6 <5.5 <5.5 47 <5.5 <5.5 <5.5 <5.5 <5.5 46 7.07.4 7.0 6.1 <5.5 48 5.9 6.2 6.1 <5.5 <5.5 65 6.7 7.3 7.1 6.0 <5.5 36 6.87.0 6.6 5.9 <5.5 32 8.7 7.9 8.2 8.1 6.6 40 7.4 7.5 7.2 6.6 5.8 35 7.37.8 7.4 6.9 5.9 29 7.8 8.5 8.2 7.3 6.2 39 6.1 6.7 6.6 5.5 <5.5 38 7.07.7 7.5 6.8 <5.5 37 7.8 8.6 8.3 7.3 6.0 41 7.0 7.5 6.9 6.1 <5.5 34 7.27.3 6.9 6.2 <5.5 33 8.3 7.8 8.1 7.6 5.8 30 6.6 7.4 7.2 6.3 <5.5 31 6.06.3 6.0 <5.5 <5.5 49 5.7 6.4 6.1 <5.5 <5.5 19 8.8 8.3 8.3 8.3 7.8 7 <6<6 <6 <6 <6

The invention claimed is:
 1. A compound selected from the groupconsisting of a compound of formula (I)

a tautomeric form, stereochemically isomeric form and isotopic formthereof, wherein W is —N(R³)— or —C(R^(3a)R^(3b))—; each R² isindependently selected from hydroxyl, halogen, cyano, C₁₋₄alkyl,C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy, hydroxyC₁₋₄alkyl,hydroxyC₁₋₄alkoxy, haloC₁₋₄alkyl, haloC₁₋₄alkoxy, hydroxyhaloC₁₋₄alkyl,hydroxyhaloC₁₋₄alkoxy, C₁₋₄alkoxyC₁₋₄alkyl, haloC₁₋₄alkoxyC₁₋₄alkyl,C₁₋₄alkoxyC₁₋₄alkyl wherein each C₁₋₄alkyl may optionally be substitutedwith one or two hydroxyl groups, hydroxyhaloC₁₋₄alkoxyC₁₋₄alkyl, R¹³,C₁₋₄alkyl substituted with R¹³, C₁₋₄alkyl substituted with —C(═O)—R¹³,C₁₋₄alkoxy substituted with R¹³, C₁₋₄alkoxy substituted with —C(═O)—R¹³,—C(═O)—R¹³, C₁₋₄alkyl substituted with —NR⁷R⁸, C₁₋₄alkyl substitutedwith —C(═O)—NR⁷R⁸, C₁₋₄alkoxy substituted with —NR⁷R⁸, C₁₋₄alkoxysubstituted with —C(═O)—NR⁷R⁸, —NR⁷R⁸ and —C(═O)—NR⁷R⁸; or when two R²groups are attached to adjacent carbon atoms they may be taken togetherto form a radical of formula:—O—(C(R¹⁷)₂)_(p)—O—;—X—CH═CH—; or—X—CH═N—; wherein R¹⁷ represents hydrogen or fluorine, p represents 1 or2 and X represents O or S; D represents a 3 to 12 ring memberedmonocyclic or bicyclic carbocyclyl or a 3 to 12 ring membered monocyclicor bicyclic heterocyclyl containing at least one heteroatom selectedfrom N, O or S, wherein said carbocyclyl and heterocyclyl may each beoptionally substituted by one or more R¹ groups; R¹ represents hydrogen,halo, cyano, C₁₋₆alkyl, C₁₋₆alkoxy, —C(═O)—O— C₁₋₆alkyl, C₂₋₄alkenyl,hydroxyC₁₋₆alkyl, haloC₁₋₆alkyl, hydroxyhaloC₁₋₆alkyl, cyanoC₁₋₄alkyl,C₁₋₆ alkoxyC₁₋₆alkyl wherein each C₁₋₆alkyl may optionally besubstituted with one or two hydroxyl groups, —NR⁴R⁵, C₁₋₆alkylsubstituted with —O—C(═O)— C₁₋₆alkyl, C₁₋₆alkyl substituted with —NR⁴R⁵,—C(═O)—NR⁴R⁵, —C(═O)—C₁₋₆alkyl-NR⁴R⁵, C₁₋₆alkyl substituted with—C(═O)—NR⁴R⁵, —S(═O)₂—C₁₋₆alkyl, —S(═O)₂-haloC₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵,C₁₋₆alkyl substituted with —S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with —S(═O)₂—NR¹⁴R¹⁵,C₁₋₆alkyl substituted with —NH—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substitutedwith —NH—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with—NR¹²—S(═O)₂—NR¹⁴R¹⁵, R⁶, C₁₋₆alkyl substituted with R⁶, —C(═O)—R⁶,C₁₋₆alkyl substituted with —C(═O)—R⁶, hydroxyC₁₋₆alkyl substituted withR⁶, C₁₋₆alkyl substituted with —Si(CH₃)₃, C₁₋₆alkyl substituted with—P(═O)(OH)₂ or C₁₋₆alkyl substituted with —P(═O)(OC₁₋₆alkyl)₂; R^(3a)represents —NR¹⁰R¹¹, hydroxyl, C₁₋₆alkoxy, hydroxyC₁₋₆alkoxy, C₁₋₆alkoxysubstituted with —NR¹⁰R¹¹, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,haloC₁₋₆alkyl optionally substituted with —O—C(═O)—C₁₋₆alkyl,hydroxyC₁₋₆alkyl optionally substituted with —O—C(═O)—C₁₋₆alkyl,hydroxyC₂₋₆alkenyl, hydroxyC₂₋₆alkynyl, hydroxyhaloC₁₋₆alkyl,cyanoC₁₋₆alkyl, C₁₋₆alkyl substituted with carboxyl, C₁₋₆alkylsubstituted with —C(═O)—C₁₋₆alkyl, C₁₋₆alkyl substituted with—C(═O)—O—C₁₋₆alkyl, C₁₋₆alkyl substituted withC₁₋₆alkoxyC₁₋₆alkyl-O—C(═O)—, C₁₋₆alkyl substituted withC₁₋₆alkoxyC₁₋₆alkyl-C(═O)—, C₁₋₆alkyl substituted with—O—C(═O)—C₁₋₆alkyl, C₁₋₆alkoxyC₁₋₆alkyl wherein each C₁₋₆alkyl mayoptionally be substituted with one or two hydroxyl groups or with—O—C(═O)—C₁₋₆alkyl, C₂₋₆alkenyl substituted with C₁₋₆alkoxy, C₂₋₆alkynylsubstituted with C₁₋₆alkoxy, C₁₋₆alkyl substituted with R⁹ andoptionally substituted with —O—C(═O)—C₁₋₆alkyl, C₁₋₆alkyl substitutedwith —C(═O)—R⁹, C₁₋₆alkyl substituted with hydroxyl and R⁹, C₂₋₆alkenylsubstituted with R⁹, C₂₋₆ alkynyl substituted with R⁹, C₁₋₆alkylsubstituted with —NR¹⁰R¹¹, C₂₋₆alkenyl substituted with —NR¹⁰R¹¹,C₂₋₆alkynyl substituted with —NR¹⁰R¹¹, C₁₋₆alkyl substituted withhydroxyl and —NR¹⁰R¹¹, C₁₋₆alkyl substituted with one or two halogensand —NR¹⁰R¹¹, —C₁₋₆alkyl-C(R¹²)═N—O—R¹², C₁₋₆alkyl substituted with—C(═O)—NR¹⁰R¹¹, C₁₋₆ alkyl substituted with —O—C(═O)—NR¹⁰R¹¹,—S(═O)₂—C₁₋₆alkyl, —S(═O)₂-haloC₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkylsubstituted with —S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with —S(═O)₂—NR¹⁴R¹⁵,C₁₋₆alkyl substituted with —NR¹²—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substitutedwith —NH—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with—NR¹²—S(═O)₂—NR¹⁴R¹⁵, R¹³, C₁₋₆alkyl substituted with —P(═O)(OH)₂ orC₁₋₆alkyl substituted with —P(═O)(OC₁₋₆alkyl)₂; R^(3b) representshydrogen or hydroxyl; provided that if R^(3a) represents —NR¹⁰R¹¹, thenR^(3b) represents hydrogen; or R^(3a) and R^(3b) are taken together toform ═O, to form ═NR¹⁰, to form cyclopropyl together with the carbonatom to which they are attached, to form ═CH—C₀₋₄alkyl substituted withR^(3c), or to form

wherein ring A is a monocyclic 5 to 7 membered saturated heterocyclecontaining one heteroatom selected from N, O or S, said heteroatom notbeing positioned in alpha position of the double bond, wherein ring A isoptionally being substituted with cyano, C₁₋₄alkyl, hydroxyC₁₋₄alkyl,H₂N—C₁₋₄alkyl, (C₁₋₄alkyl)NH—C₁₋₄alkyl, (C₁₋₄alkyl)₂N—C₁₋₄alkyl,(haloC₁₋₄alkyl)NH—C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, —C(═O)—NH₂,—C(═O)—NH(C₁₋₄alkyl), —C(═O)—N(C₁₋₄alkyl)₂; R^(3c) represents hydrogen,hydroxyl, C₁₋₆alkoxy, R⁹, —NR¹⁰R¹¹, —C(═O)—NR¹⁴R¹⁵, cyano,—C(═O)—C₁₋₆alkyl or —CH(OH)— C₁₋₆alkyl; R³ represents hydroxyl,C₁₋₆alkoxy, hydroxyC₁₋₆alkoxy, C₁₋₆alkoxy substituted with —NR¹⁰R¹¹,C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, haloC₁₋₆alkyl optionallysubstituted with —O—C(═O)—C₁₋₆alkyl, hydroxyC₁₋₆alkyl optionallysubstituted with —O—C(═O)—C₁₋₆alkyl, hydroxyC₂₋₆alkenyl,hydroxyC₂₋₆alkynyl, hydroxyhaloC₁₋₆alkyl, cyanoC₁₋₆alkyl, C₁₋₆alkylsubstituted with carboxyl, C₁₋₆alkyl substituted with —C(═O)—C₁₋₆alkyl,C₁₋₆alkyl substituted with —C(═O)—O—C₁₋₆alkyl, C₁₋₆alkyl substitutedwith C₁₋₆alkoxyC₁₋₆alkyl-O—C(═O)—, C₁₋₆alkyl substituted withC₁₋₆alkoxyC₁₋₆alkyl-C(═O)—, C₁₋₆alkyl substituted with—O—C(═O)—C₁₋₆alkyl, C₁₋₆alkoxyC₁₋₆alkyl wherein each C₁₋₆alkyl mayoptionally be substituted with one or two hydroxyl groups or with—O—C(═O)—C₁₋₆alkyl, C₂₋₆alkenyl substituted with C₁₋₆alkoxy, C₂₋₆alkynylsubstituted with C₁₋₆alkoxy, C₁₋₆alkyl substituted with R⁹ andoptionally substituted with —O—C(═O)—C₁₋₆alkyl, C₁₋₆alkyl substitutedwith —C(═O)—R⁹, C₁₋₆alkyl substituted with hydroxyl and R⁹, C₂₋₆alkenylsubstituted with R⁹, C₂₋₆alkynyl substituted with R⁹, C₁₋₆alkylsubstituted with —NR¹⁰R¹¹, C₂₋₆alkenyl substituted with —NR¹⁰R¹¹,C₂₋₆alkynyl substituted with —NR¹⁰R¹¹, C₁₋₆alkyl substituted withhydroxyl and —NR¹⁰R¹¹, C₁₋₆alkyl substituted with one or two halogensand —NR¹⁰R¹¹, —C₁₋₆alkyl-C(R¹²)═N—O—R¹², C₁₋₆alkyl substituted with—C(═O)—NR¹⁰R¹¹, C₁₋₆ alkyl substituted with —O—C(═O)—NR¹⁰R¹¹,—S(═O)₂—C₁₋₆alkyl, —S(═O)₂-haloC₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkylsubstituted with —S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with —S(═O)₂—NR¹⁴R¹⁵,C₁₋₆alkyl substituted with —NR¹²—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substitutedwith —NH—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with—NR¹²—S(═O)₂—NR¹⁴R¹⁵, R¹³, C₁₋₆alkyl substituted with —P(═O)(OH)₂ orC₁₋₆alkyl substituted with —P(═O)(OC₁₋₆alkyl)₂; R⁴ and R⁵ eachindependently represent hydrogen, C₁₋₆alkyl, C₁₋₆alkyl substituted with—NR¹⁴R¹⁵, hydroxyC₁₋₆alkyl, haloC₁₋₆alkyl, hydroxyhaloC₁₋₆alkyl,C₁₋₆alkoxyC₁₋₆alkyl wherein each C₁₋₆alkyl may optionally be substitutedwith one or two hydroxyl groups, —S(═O)₂—C₁₋₆alkyl,—S(═O)₂-haloC₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵, —C(═O)—NR¹⁴R¹⁵, —C(═O)—O—C₁₋₆alkyl, —C(═O)—R¹³, C₁₋₆alkyl substituted with —S(═O)₂—C₁₋₆alkyl,C₁₋₆alkyl substituted with —S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substitutedwith —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with —NH—S(═O)₂—C₁₋₆alkyl,C₁₋₆alkyl substituted with —NH—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkylsubstituted with —NH—S(═O)₂—NR¹⁴R¹⁵, R¹³ or C₁₋₆alkyl substituted withR¹³; R⁶ represents C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, phenyl, 4 to7-membered monocyclic heterocyclyl containing at least one heteroatomselected from N, O or S; said C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, phenyl,4 to 7-membered monocyclic heterocyclyl, optionally and eachindependently being substituted by 1, 2, 3, 4 or 5 substituents, eachsubstituent independently being selected from cyano, C₁₋₆alkyl,cyanoC₁₋₆alkyl, hydroxyl, carboxyl, hydroxyC₁₋₆alkyl, halogen,haloC₁₋₆alkyl, hydroxyhaloC₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkoxyC₁₋₆alkyl,C₁₋₆alkyl-O—C(═O)—, —NR¹⁴R¹⁵, —C(═O)—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with —C(═O)—NR¹⁴R¹⁵, —S(═O)₂—C₁₋₆alkyl,—S(═O)₂-haloC₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with —S(═O)₂-haloC₁₋₆alkyl,C₁₋₆alkyl substituted with —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with—NH—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with—NH—S(═O)₂-haloC₁₋₆alkyl or C₁₋₆alkyl substituted with—NH—S(═O)₂—NR¹⁴R¹⁵; R⁷ and R⁸ each independently represent hydrogen,C₁₋₆alkyl, hydroxyC₁₋₆alkyl, haloC₁₋₆alkyl, hydroxyhaloC₁₋₆alkyl orC₁₋₆alkoxyC₁₋₆alkyl; R⁹ represents C₃₋₈ cycloalkyl, C₃₋₈ cycloalkenyl,phenyl, naphthyl, or 3 to 12 membered monocyclic or bicyclicheterocyclyl containing at least one heteroatom selected from N, O or S,said C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, phenyl, naphthyl, or 3 to 12membered monocyclic or bicyclic heterocyclyl each optionally and eachindependently being substituted with 1, 2, 3, 4 or 5 substituents, eachsubstituent independently being selected from ═O, C₁₋₄alkyl, hydroxyl,carboxyl, hydroxyC₁₋₄alkyl, cyano, cyanoC₁₋₄alkyl, C₁₋₄alkyl-O—C(═O)—,C₁₋₄alkyl substituted with C₁₋₄alkyl-O—C(═O)—, C₁₋₄alkoxyC₁₋₄alkylwherein each C₁₋₄alkyl may optionally be substituted with one or twohydroxyl groups, halogen, haloC₁₋₄alkyl, hydroxyhaloC₁₋₄alkyl, —NR¹⁴R¹⁵,—C(═O)—NR¹⁴R¹⁵, C₁₋₄alkyl substituted with —NR¹⁴R¹⁵, C₁₋₄alkylsubstituted with —C(═O)—NR¹⁴R¹⁵, C₁₋₄ alkoxy, —S(═O)₂—C₁₋₄alkyl,—S(═O)₂-haloC₁₋₄alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₄alkyl substituted with—S(═O)₂—NR¹⁴R¹⁵, C₁₋₄alkyl substituted with —NH—S(═O)₂—C₁₋₄alkyl,C₁₋₄alkyl substituted with —NH—S(═O)₂-haloC₁₋₄alkyl, C₁₋₄alkylsubstituted with —NH—S(═O)₂—NR¹⁴R¹⁵, R¹³, —C(═O)—R¹³, C₁₋₄alkylsubstituted with R¹³, phenyl optionally substituted with R¹⁶,phenylC₁₋₆alkyl wherein the phenyl is optionally substituted with R¹⁶, a5 or 6-membered aromatic monocyclic heterocyclyl containing at least oneheteroatom selected from N, O or S wherein said heterocyclyl isoptionally substituted with R¹⁶; or when two of the substituents of R⁹are attached to the same atom, they may be taken together to form a 4 to7-membered saturated monocyclic heterocyclyl containing at least oneheteroatom selected from N, O or S; R¹⁰ and R¹¹ each independentlyrepresent hydrogen, carboxyl, C₁₋₆alkyl, cyanoC₁₋₆alkyl, C₁₋₆alkylsubstituted with NR¹⁴R¹⁵, C₁₋₆alkyl substituted with C(═O)—NR¹⁴R¹⁵,haloC₁₋₆alkyl, hydroxyC₁₋₆alkyl, hydroxyhaloC₁₋₆alkyl, C₁₋₆alkoxy,C₁₋₆alkoxyC₁₋₆alkyl wherein each C₁₋₆alkyl may optionally be substitutedwith one or two hydroxyl groups, R⁶, C₁₋₆alkyl substituted with R⁶,—C(═O)—R⁶, —C(═O)—C₁₋₆alkyl, —C(═O)-hydroxyC₁₋₆alkyl,—C(═O)-haloC₁₋₆alkyl, —C(═O)-hydroxyhaloC₁₋₆alkyl, C₁₋₆alkyl substitutedwith —Si(CH₃)₃, —S(═O)₂—C₁₋₆alkyl, —S(═O)₂-haloC₁₋₆alkyl,—S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with —S(═O)₂—C₁₋₆alkyl, C₁₋₆alkylsubstituted with —S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with—S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with —NH—S(═O)₂—C₁₋₆alkyl,C₁₋₆alkyl substituted with —NH—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkylsubstituted with carboxyl, or C₁₋₆alkyl substituted with—NH—S(═O)₂—NR¹⁴R¹⁵; R¹² represents hydrogen or C₁₋₄alkyl optionallysubstituted with C₁₋₄alkoxy; R¹³ represents C₃₋₈cycloalkyl or asaturated 4 to 6-membered monocyclic heterocyclyl containing at leastone heteroatom selected from N, O or S, wherein said C₃₋₈ cycloalkyl ormonocyclic heterocyclyl is optionally substituted with 1, 2 or 3substituents each independently selected from halogen, hydroxyl,C₁₋₆alkyl, haloC₁₋₆alkyl, ═O, cyano, —C(═O)—C₁₋₆alkyl, C₁₋₆alkoxy, or—NR¹⁴R¹⁵; R¹⁴ and R¹⁵ each independently represent hydrogen, orhaloC₁₋₄alkyl, or C₁₋₄alkyl optionally substituted with a substituentselected from hydroxyl, C₁₋₄alkoxy, amino or mono- ordi(C₁₋₄alkyl)amino; R¹⁶ represents hydroxyl, halogen, cyano, C₁₋₄alkyl,C₁₋₄alkoxy, —NR¹⁴R¹⁵ or C(═O)NR¹⁴R¹⁵; and n independently represents aninteger equal to 0, 1, 2, 3 or 4; or an N-oxide thereof, apharmaceutically acceptable salt thereof or a solvate thereof.
 2. Acompound according to claim 1 wherein D is optionally substitutedpyrazolyl; or an N-oxide thereof, a pharmaceutically acceptable saltthereof or a solvate thereof.
 3. A compound according to claim 1 whereinW is —N(R³)—; or an N-oxide thereof, a pharmaceutically acceptable saltthereof or a solvate thereof.
 4. A compound according to claim 1 whereinW is —C(R^(3a)R^(3b))—; or an N-oxide thereof, a pharmaceuticallyacceptable salt thereof or a solvate thereof.
 5. A compound according toclaim 1 wherein R¹ represents C₁₋₆alkyl; or an N-oxide thereof, apharmaceutically acceptable salt thereof or a solvate thereof.
 6. Acompound according to claim 1 wherein R² represents C₁₋₄alkoxy or halo;or an N-oxide thereof, a pharmaceutically acceptable salt thereof or asolvate thereof.
 7. A compound according to claim 1 wherein R³represents hydroxyC₁₋₆alkyl, C₁₋₆alkyl substituted with —NR¹⁰R¹¹ orC₁₋₆alkyl substituted with R⁹; or an N-oxide thereof, a pharmaceuticallyacceptable salt thereof or a solvate thereof.
 8. A compound according toclaim 1 wherein D is pyrazolyl or phenyl, each optionally substitutedwith C₁₋₄alkyl; W is —N(R³)— or —C(═O)—; R³ is hydroxyC₁₋₆alkyl,C₁₋₆alkyl substituted with R⁹, or C₁₋₆alkyl substituted with —NR¹⁰R¹¹;R⁹ is imidazolyl optionally substituted with —S(═O)₂—NR¹⁴R¹⁵; R¹⁰ andR¹¹ each independently represent hydrogen or C₁₋₆ alkyl; and R¹⁴ and R¹⁵represent C₁₋₄alkyl; or an N-oxide thereof, a pharmaceuticallyacceptable salt thereof or a solvate thereof.
 9. A compound according toclaim 1 wherein W is —N(R³)— or —C(═O); each R² is halogen orC₁₋₄alkoxy; D represents a 5 to 6 ring membered monocyclic carbocyclylor a 5 to 6 ring membered monocyclic heterocyclyl containing at leastone heteroatom selected from N, O or S, wherein said carbocyclyl andheterocyclyl may each be optionally substituted by one or more R¹groups; R¹ represents C₁₋₆alkyl; R³ represents hydroxyC₁₋₆alkyl,C₁₋₆alkyl substituted with R⁹, or C₁₋₆alkyl substituted with —NR¹⁰R¹¹;R⁹ represents a 5 membered monocyclic heterocyclyl containing at leastone heteroatom selected from N, O or S, said 5 membered monocyclicheterocyclyl optionally substituted with —S(═O)₂—NR¹⁴R¹⁵; R¹⁰ and R¹¹each independently represent hydrogen or C₁₋₆ alkyl; R¹⁴ and R¹⁵represent C₁₋₄alkyl; and n independently represents an integer equal to1, 2, 3 or 4; or an N-oxide thereof, a pharmaceutically acceptable saltthereof or a solvate thereof.
 10. A compound according to claim 1wherein W is —N(R³)— or —C(R^(3a)R^(3b))—; each R² is halogen orC₁₋₄alkoxy; D represents a 5 to 6 ring membered monocyclic carbocyclylor a 5 to 6 ring membered monocyclic heterocyclyl containing at leastone heteroatom selected from N, O or S, wherein said carbocyclyl andheterocyclyl may each be optionally substituted by one or more R¹groups; R¹ represents C₁₋₆alkyl or —C(═O)—O—C₁₋₆alkyl; R³ representshydroxyC₁₋₆alkyl, C₁₋₆alkyl substituted with R⁹, or C₁₋₆alkylsubstituted with —NR¹⁰R¹¹; R^(3a) and R^(3b) are taken together to form═O or ═CH—C₀₋₄alkyl substituted with R^(3c); R^(3c) is cyano; R⁹represents a 5 membered monocyclic heterocyclyl containing at least oneheteroatom selected from N, O or S, said 5 membered monocyclicheterocyclyl optionally substituted with —S(═O)₂—NR¹⁴R¹⁵; R¹⁰ and R¹¹each independently represent hydrogen or C₁₋₆ alkyl; R¹⁴ and R¹⁵represent C₁₋₄alkyl; and n independently represents an integer equal to1, 2, 3 or 4; or an N-oxide thereof, a pharmaceutically acceptable saltthereof or a solvate thereof.
 11. A compound according to claim 1wherein the compound is

or an N-oxide thereof, a pharmaceutically acceptable salt thereof or asolvate thereof.
 12. A compound according to claim 1 or apharmaceutically acceptable salt or solvate thereof.
 13. A compoundaccording to claim 11 or a pharmaceutically acceptable salt or solvatethereof.
 14. A pharmaceutical composition comprising a compoundaccording to claim 1 or an N-oxide thereof, a pharmaceuticallyacceptable salt thereof or a solvate thereof.
 15. A pharmaceuticalcomposition comprising a compound according to claim 11 or an N-oxidethereof, a pharmaceutically acceptable salt thereof or a solvatethereof.
 16. A combination comprising a compound according to claim 1,or an N-oxide thereof, a pharmaceutically acceptable salt thereof or asolvate thereof, and another anticancer agent.
 17. A method ofinhibiting a FGFR kinase, which method comprises contacting the kinasewith a compound according to claim 1 or an N-oxide thereof, apharmaceutically acceptable salt thereof or a solvate thereof.
 18. Amethod of inhibiting a FGFR kinase, which method comprises contactingthe kinase with a compound according to claim 11 or an N-oxide thereof,a pharmaceutically acceptable salt thereof or a solvate thereof.
 19. Amethod for the treatment of cancer, which method comprises administeringto a subject in need thereof a compound according to claim 1 or anN-oxide thereof, a pharmaceutically acceptable salt thereof or a solvatethereof.
 20. A method for the treatment of a disease state or conditionmediated by a FGFR kinase, which method comprises administering to asubject in need thereof a compound according to claim 1 or an N-oxidethereof, a pharmaceutically acceptable salt thereof or a solvatethereof.